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Mol Med. 2011 Nov-Dec; 17(11-12): 1383–1396.
Published online Aug 4, 2011. doi:  10.2119/molmed.2011.00195
PMCID: PMC3321806
Selective IgA Deficiency in Autoimmune Diseases
Ning Wang,1 Nan Shen,2 Timothy J Vyse,3 Vidya Anand,3 Iva Gunnarson,4 Gunnar Sturfelt,5 Solbritt Rantapää-Dahlqvist,6 Kerstin Elvin,7 Lennart Truedsson,8 Bengt A Andersson,9 Charlotte Dahle,10 Eva Örtqvist,11 Peter K Gregersen,12 Timothy W Behrens,13 and Lennart Hammarström1
1Division of Clinical Immunology, Department of Laboratory Medicine, Karolinska Institutet at Karolinska University Hospital Huddinge, Stockholm, Sweden
2Department of Rheumatology, Renji Hospital, JiaoTong University School of Medicine, Shanghai, China
3Section of Molecular Genetics and Rheumatology, Hammersmith Hospital, London, United Kingdom
4Rheumatology Unit, Department of Medicine, Karolinska University Hospital Solna, Stockholm, Sweden
5Department of Rheumatology, Lund University Hospital, Lund, Sweden
6Department of Rheumatology, University Hospital, Umeå, Sweden
7Unit of Clinical Immunology, Department of Clinical Immunology and Transfusion Medicine, Karolinska University Hospital Huddinge, Stockholm, Sweden
8Department of Laboratory Medicine, Section of Microbiology, Immunology and Glycobiology, Lund University, Sweden
9Department of Immunology, Sahlgrenska Academy, Gothenburg, Sweden
10Clinical Immunology Unit, Department of Clinical and Experimental Medicine, Linköping University, Linköping, Sweden
11Department of Woman and Child Health, Astrid Lindgren Children’s Hospital, Karolinska University Hospital Solna, Stockholm, Sweden
12Robert S. Boas Center for Genomics and Human Genetics, Feinstein Institute for Medical Research, Manhasset, New York, United States of America
13Division of Immunology, Tissue Growth & Repair, Biomarker Discovery and Human Genetics, Genentech, South San Francisco, California, United States of America
Address correspondence and reprint requests to Lennart Hammarström, Division of Clinical Immunology, Department of Laboratory Medicine, Karolinska Institutet at Karolinska University Hospital Huddinge, 141 86 Stockholm, Sweden. Phone: +46-8-524-835-86; Fax: +46-8-524-835-88; E-mail: lennart.hammarstrom/at/ki.se.
Received May 31, 2011; Accepted August 2, 2011.
Selective immunoglobulin A deficiency (IgAD) is the most common primary immunodeficiency in Caucasians. It has previously been suggested to be associated with a variety of concomitant autoimmune diseases. In this review, we present data on the prevalence of IgAD in patients with Graves disease (GD), systemic lupus erythematosus (SLE), type 1 diabetes (T1D), celiac disease (CD), myasthenia gravis (MG) and rheumatoid arthritis (RA) on the basis of both our own recent large-scale screening results and literature data. Genetic factors are important for the development of both IgAD and various autoimmune disorders, including GD, SLE, T1D, CD, MG and RA, and a strong association with the major histocompatibility complex (MHC) region has been reported. In addition, non-MHC genes, such as interferon-induced helicase 1 (IFIH1) and c-type lectin domain family 16, member A (CLEC16A), are also associated with the development of IgAD and some of the above diseases. This indicates a possible common genetic background. In this review, we present suggestive evidence for a shared genetic predisposition between these disorders.
Selective immunoglobulin A deficiency (IgAD) is the most common primary immunodeficiency with a frequency of 1 in 600 in Caucasians (1). The prevalence in various ethnic groups ranges from 1:155 in Spain (2) to 1:18,550 in Japan (3) (for additional data, see refs. 4 and 5). The current definition, established by the Pan-American Group for Immunodeficiency and the European Society for Immunodeficiencies, defines the disorder as serum IgA levels <0.07 g/L with normal IgM and IgG levels in individuals ≥4 years of age (6).
Most individuals with IgAD are clinically asymptomatic, but the defect may be associated with recurrent respiratory and gastrointestinal tract infections/disorders, autoimmunity and allergies. Patients with IgAD are usually more prone to infections when concomitant IgG subclass deficiency is present (7).
IgAD is strongly associated with the major histocompatibility complex (MHC) region, in particular with the human leukocyte antigen (HLA)-B8, DR3, DQ2 (8.1) haplotype (8,9), and up to 45% of IgAD patients have at least one copy of this haplotype compared to 16% in the general population (10). Homozygosity for the ancestral 8.1 haplotype increases the risk of development of the disease even further (10). Other haplotypes, including HLA-DR7, DQ2 and DR1, DQ5 are also associated with IgAD (11). In contrast, the DR15, DQ6 haplotype has been shown to confer an almost complete protection against the disorder (1214). Polymorphisms in the non-MHC genes interferon-induced helicase 1 (IFIH1) and c-type lectin domain family 16, member A (CLEC16A) genes have also been shown to be associated with IgAD in a recent genome-wide association study (GWAS) (13).
Interestingly, the ancestral 8.1 haplo-type is also reported to be associated with Graves disease (GD), systemic lupus erythematosus (SLE), type 1 diabetes (T1D) and celiac disease (CD) (15,16). In addition, telomeric portions of this haplotype have also been shown to contain a risk factor for myasthenia gravis (MG) (17) and rheumatoid arthritis (RA) (18). Moreover, there are several non-MHC genes in common that have also been shown to be associated with these autoimmune disorders. It is therefore possible that IgAD and selected autoimmune disorders share some of the predisposing genes, thus explaining the increased prevalence of IgAD in certain patient groups.
IgAD and Graves Disease
GD is one of the most prevalent autoimmune thyroid disorders (19). GD is characterized by lymphocytic infiltration of the thyroid gland and production of thyrotropin-receptor autoantibodies (TRAbs), leading to hyperthyroidism (20). TRAb, which is found in >95% of newly diagnosed GD patients (21), has been shown to be the main contributor to the onset and maintenance of GD. The incidence rates of GD have increased significantly and are roughly 29–30/100,000 annually in Caucasians (22), while an incidence of 14/100,000 has been reported in China (23). The seasonal trend and the geographical variation in the incidence of GD suggest that infections might be an important contributing factor to the pathogenesis of the disease (20). Twin studies have reported a concordance rate of 35% in monozygotic (MZ) compared to 3% in dizygotic (DZ) twins (reviewed in [24]), and the sibling risk ratio for GD is increased (25), indicating a strong genetic influence on the development of the disease.
GD was initially found to be associated with the HLA-B8 allele in Caucasians (24,26). However, subsequent study suggested that the primary susceptibility allele is the DR3 allele (27), with a frequency of approximately 40–55% in GD patients (26). However, because of the pronounced linkage disequilibrium, the exact location on the extended HLA-A1, B8, DR3 haplotype cannot be pinpointed. In addition, the HLA-DQA1*0501 allele was also shown to be associated with GD in Caucasians (28,29), as have non-MHC genes, including cytotoxic T-lymphocyte-associated protein 4 (CTLA4); CD40; protein tyrosine phosphatase, non-receptor type 22 (PTPN22); thyroglobulin and thyroid stimulating hormone receptor (TSHR) (30,31).
An association between GD and IgAD was previously suggested in various case reports (3235), and a small screening study showed that IgAD is overrepresented among GD patients (36) (Table 1), although this could not be confirmed by other groups (3739).
Table 1
Table 1
Prevalence of IgAD among GD patients.
We recently investigated the association of IgAD with GD, defined by elevated serum levels of TRAb, in Icelandic and Swedish patients (15). The data showed a markedly higher prevalence of IgAD in the Swedish cohort (see Table 1). Furthermore, the prevalence of TRAb positivity in IgAD patients was increased in both cohorts (1:60, P = 0.006), suggesting a significant association of IgAD with GD. In addition, of the five GD patients with IgAD where DNA could be obtained, four carried the HLA-DR3, DQ2 haplotype (15).
IgAD and Systemic Lupus Erythematosus
Systemic lupus erythematosus (SLE) is a systemic autoimmune disease that is characterized by a diverse array of autoantibodies, immune complex deposition, complement activation and tissue injury, influenced by multiple genetic and environmental factors. It predominantly affects women (prevalence ratio of women to men is 9:1), particularly during the child-bearing years (40). The prevalence of SLE varies among different ethnic groups, ranging from 7 to 71 cases per 100,000 people of European descent (68/100,000 in Sweden [41]), 31 to 70 cases per 100,000 people among Chinese populations (40) and >200 per 100,000 people of African descent (42). The concordance rates within pairs of MZ twins range from 20% to 40% compared with 2% to 5% for DZ twins (43,44). Furthermore, the risk of SLE is increased both in first- and second-degree relatives (43,44), suggesting a strong genetic basis of the disease.
An association with the HLA-DR region, in particular, the HLA-DRB1*0301 and HLA-DRB1*1501 alleles (12,45,46), was reported in SLE patients of European ancestry, whereas DR2 (DRB1*1501) was overrepresented among Asian patients (4749). Genes within the class III region of the MHC, including mutS homolog 5 (MSH5) (50) and superkiller viralicidic activity 2-like (SKIV2L) (51), have also been suggested to constitute risk factors for the disease. Furthermore, SLE is associated with a variety of non-MHC genes, including three prime repair exonuclease 1 (TREX1); tumor necrosis factor, alpha-induced protein 3 (TNFAIP3); interferon regulatory factor 5 (IRF5); integrin, alpha M (ITGAM); signal transducer and activator of transcription 4 (STAT4); B lymphoid tyrosine kinase (BLK); B-cell scaffold protein with ankyrin repeats 1 (BANK1); PTPN22; tumor necrosis factor superfamily, member 4 (TNFSF4); PX domain containing serine/threonine kinase (PXK) and interleukin-1 receptor-associated kinase 1(IRAK1) (reviewed in [52]).
Previous studies have reported an increased frequency of IgAD among SLE patients, ranging from 1:19 in the USA to 1:130 in Spain (Table 2) (5363). There have also been several case reports on the association between IgAD and SLE (6472). However, the total number of patients screened for IgAD is still quite limited, and the criteria used to define IgAD have been variable. We thus determined the frequency of IgAD among 3388 SLE patients in Sweden, the UK, the USA and China, using an enzyme-linked immunosorbent assay to measure the serum IgA levels (for protocol, see [5]). IgAD was identified in a total of 44 patients, giving a total frequency of 1:67 in Caucasians and 1:121 in Chinese (see Table 2). Interestingly, the prevalence of IgAD among the Chinese SLE patients was >30-fold higher than in the general Chinese population (1:4,146) (73), indicating a strong association between these two diseases regardless of ethnic origin (P < 2 × 10−16).
Table 2
Table 2
Prevalence of IgAD among SLE patients.
Available samples of SLE patients with IgAD were genotyped at the HLA-B, -DR and -DQ loci using a sequence-specific primed polymerase chain reaction (PCR-SSP) (Olerup SSP, Saltjöbaden, Sweden). All Swedish SLE patients with IgAD (n = 6) carried the HLA-B8, DR3, DQ2 haplotype in a heterozygous form. Of the five English SLE patients, one patient was homozygous for the HLA-B8, DR3, DQ2 haplotype and one was homozygous for the DR3 allele. However, the HLA alleles of Chinese SLE patients did not conform to the known Caucasian risk alleles either for IgAD or SLE.
IgAD and Type 1 Diabetes
Type 1 diabetes (T1D) is a chronic auto-immune disorder characterized by destruction of insulin-producing β cells in the pancreas, leading to reduced/absent insulin production. The damage is primarily due to a cell-mediated response, effectuated by activated cytotoxic T cells (CD8+). T1D affects approximately 0.4% of people of European origin (74), but the incidence rate varies greatly between different parts of the world, ranging from 0.6 cases per 100,000 per year in Korea (75) to 40.2 cases per 100,000 per year in selected regions in Finland (76). Furthermore, the incidence of T1D is rising at a rate of 3–5% per year (77,78). Both genetic and environmental factors, including infections, socioeconomic status and nutrition (7981), influence the development of the disorder. The concordance rate for T1D in MZ twins is approximately 50% (8285), and in a recently published, prospective, long-term follow-up study of MZ twins, a cumulative incidence of 65% was reported (86). Furthermore, the prevalence of T1D in first-degree relatives is markedly higher than in the general population (87,88). Taken together, these studies suggest that the genetic predisposition may be even more important than previously recognized for the development of T1D.
It is commonly accepted that the MHC class II locus is the most important determinant for T1D (89). The predisposing MHC class II haplotypes, DRB1*0301-DQB1*0201 (DR3, DQ2) and DRB1*0401-DQB1*0302 (DR4, DQ8), are present in at least 90% of cases (90). Other susceptibility genes/regions within the MHC region have also been suggested, including the class I HLA-A and -B regions (91), the class II HLA-DRA and -DPB1 regions (91) and notch 4 (NOTCH4) and MSH5 in the class III region (92). Furthermore, a variety of non-MHC region genes have been previously shown to be associated with T1D, including insulin (INS); (CTLA4); (PTPN22); interleukin 2 receptor alpha (IL2RA); SH2B adaptor protein 3 (SH2B3); CLEC16A; IFIH1 and protein tyrosine phosphatase, non-receptor type 2 (PTPN2) (reviewed in [93]).
The prevalence of IgAD in T1D has been reported to range from 1:27 (94) to 1:261 (95) in several reports, although no cases were observed in three studies (9698) (Table 3), indicating an increased frequency compared to the general population. We measured IgA serum levels in three separate cohorts of T1D patients (children and adults) in Italy and Sweden. Our own data show a prevalence of IgAD of 1:114 in Sweden and 1:122 in Italy (see Table 3), giving an overall prevalence of 1:100 in Caucasians (a roughly fivefold increase compared to the general population). Of the 11 Swedish T1D patients with concomitant IgAD, 3 were homozygous for the HLA-B8, DR3, DQ2 haplotype; 7 carried a copy of the B8, DR3, DQ2 haplotype; and 1 patient carried a copy of the B18, DR3, DQ2 haplotype. None of the two Italian T1D patients with IgAD carried the DR3, DQ2 haplotype.
Table 3
Table 3
Prevalence of IgAD among T1D patients.
IgAD and Celiac Disease
Celiac disease (CD) is a chronic inflammatory disorder of the intestinal tract, characterized by villous atrophy, crypt hyperplasia and inflammation in the small bowel. The disease is due to an immune reaction against gluten and related proteins found in wheat, rye and barley. The damage is mainly caused by intestinal intraepithelial lymphocyte-mediated cytotoxicity, and, already in 1975, Ferguson et al. reported that a local cell-mediated immunity reaction to gluten causes villous atrophy (99). The prevalence of CD among adults and children is approximately 1% (100104). The disease is recognized in almost the entire world. The Saharawi population in Algeria has the highest prevalence (5.6%) (105), and CD appears to be rare in individuals of Japanese and Chinese ancestry (106). In Europe, the highest prevalence was reported in Finland (2.4%) and the lowest in Germany (0.3%) (107). These differences might be explained by genetic, environmental and social factors. Genetic factors play a key role in the development of CD, as shown by familial aggregation (5–15%) and a high concordance rate in MZ twins (83–86%) compared to DZ twins (17–20%) (108,109).
CD is strongly associated with genes within the MHC class II region, as almost all patients carry HLA-DQ2 and/or -DQ8. The HLA-DQ2 allele, which shows the strongest association with CD, is often encoded together with HLA-B8 and HLA-DR3 on the ancestral 8.1 haplotype. HLA-DQ2 is present in 20–30% of the general population but only 1–3% of all individuals carrying HLA-DQ2 develop CD (110). HLA-DQ8 is present in approximately 18.7% of the general population; however, only 0.1–0.3% of individuals carrying this allele develop CD. Thus, presence of HLA-DQ2 or HLA-DQ8 is a necessary, but not sufficient, prerequisite for developing the disease (111). Non-HLA genes, including regulator of G-protein signaling 1 (RGS1); toll-like receptor 7/8 (TLR7/TLR8); chemokine (C-C motif) receptor 4 (CCR4); parkinson protein 7 (PARK7); runt-related transcription factor 3 (RUNX3); nuclear factor I/A (NFIA); T-cell activation RhoGTPase activating protein (TAGAP) and CD80, were also reported to be specifically involved in CD (112), whereas genetic loci shared with other autoimmune diseases include SH2B3; IRF4; v-rel reticuloendotheliosis viral oncogene homolog (REL); PTPN2; zinc finger, MIZ-type containing 1 (ZMIZ1) and CTLA4 (reviewed in [112]).
IgAD was previously shown to be associated with CD (113118), with a reported overall prevalence of 1:39 (Table 4), indicating a 5- to 15-fold increase in the prevalence of IgAD among both children and adults with CD. Conversely, several studies have also shown an increased prevalence of CD among IgAD patients (119123). Furthermore, two studies demonstrated a higher prevalence of IgAD among patients with suspected CD (118,124).
Table 4
Table 4
Prevalence of IgAD among CD patients.
We recently investigated the association between IgAD and CD in 442,225 individuals in Sweden, referred to immunology centers between 1998 and 2010 because of suspected CD. The patients were screened for anti- endomysium and/or anti-gliadin and anti-transglutaminase (TTG) antibodies, and total serum IgA levels were measured at the time of the investigation.
The frequency of positive anti-TTG samples among the IgA-sufficient patients tested in our own clinic (IgA anti-TTG) during the period 2006–2011 was 1.9% (351 out of 18,811 samples from unique patients). However, the diagnostic accuracy varies during the time period, with 3.6% of positive samples in 2011 (120 out of 3,321 samples from unique patients). Because there is a high degree of concordance between IgA and IgG anti-TTG levels (125127), the positive samples observed above would also be expected to be positive for IgG anti-TTG antibodies. In IgAD patients, IgG anti-TTG, rather than IgA anti-TTG, serves as a marker for CD with a high sensitivity and specificity (128). The prevalence of IgG anti-TTG among IgAD blood donors ranges from 8.7% to 9.8% (123,128), with the prevalence of 9.3% in our own IgAD blood donor cohort (n = 43). However, among patients with IgAD, referred for anti-TTG screening due to gastrointestinal symptoms, the frequency of positive samples was markedly higher (16.6 %) (61 out of 367 samples from unique patients).
Altogether, 971 children and 1,338 adults with IgAD were identified, giving a frequency of 1:192. Of the hitherto re-sampled 394 individuals, 92% were shown to have IgAD, and the remaining cases were found to have additional antibody defects (common variable immunodeficiency). CD was confirmed in 58 of the 86 IgAD cases that were biopsied, whereas 28 were negative. A total of 46 of the former patients were HLA typed and 40 of them carried one copy of the DQ2 allele (87%), whereas the remaining carried one copy of DQ3 (a broad specificity including DQ8), suggesting that CD patients with IgAD have a similar HLA-DQ distribution as IgA-sufficient CD patients.
IgAD and Myasthenia Gravis
Myasthenia gravis (MG) is an antibody-mediated disorder where autoantibodies against the acetylcholine receptor (anti-AChR antibodies) disrupt normal signal transduction across the neuromuscular junction in the vast majority of cases (129). Anti-MuSK (muscle-specific kinase) antibodies may also be detected in patients without anti-AChR (130). The loss of muscle receptors and the resulting reduction of signal transduction from nerve cells to muscle cells cause muscle weakness. Several autoimmune disorders, such as SLE (131133), RA (134), and GD (134137), have previously been shown to be overrepresented among patients with MG. The prevalence of MG is approximately 10 per 100,000 in European populations (14.1/100,000 in Sweden [138]) and an incidence of 0.3–3 cases per 100,000 per year (139). The rate of concordance is approximately 35% in MZ and 4–5% in DZ twins (140), indicating a strong genetic component.
The MHC region is reported to be associated with MG (17,141,142). Early-onset MG and patients exhibiting thymic hyperplasia are most strongly associated with the HLA-B8, DR3 haplotype, and late-onset MG is associated with B7 and DR2 alleles (143,144). Non-MHC genes are also known to be associated with MG, including interleukin (IL)-1; CTLA4; IL-10, tumor necrosis factor (TNF)-α; cholinergic receptor, nicotinic, alpha 1 (CHRNA-1) and PTPN22 (reviewed in [145]).
Studies on the frequency of IgAD in cohorts of patients with MG are presented in Table 5. The prevalence of IgAD is slightly elevated from the background rate, although two separate UK reports with 1 IgAD patient in 50 and 54 individuals, respectively, account for a large proportion of the increase. In another study (n = 333), the frequency of IgAD was not significantly increased, with only one patient being IgAD.
Table 5
Table 5
Prevalence of IgA deficiency among MG patients.
We recently investigated the prevalence of IgAD in 512 Swedish MG patients by measuring serum IgA levels using nephelometry. Two IgAD individuals were identified (P = 0.19) (14). Combined with previous studies, 5 of 1,107 G patients screened were classified as IgAD (1:221). Despite a strong overlap of the HLA-B8, DR3, DQ2 haplotype, the prevalence of IgAD is thus not markedly increased in MG patients.
IgAD and RA
RA is a chronic inflammation, mainly of the synovial joints. Diagnosis is made for patients exhibiting 6 of 10 criteria of the ACR/EULAR Rheumatoid Arthritis Classification Criterion (146). Many patients exhibit increased levels of rheumatoid factor and antibodies against cyclic citrullinated protein. Juvenile rheumatoid arthritis (JRA), also termed juvenile idiopathic arthritis, typically appears from 6 months to 16 years of age (147). The condition in children appears to differ from that in adults, although definitive causes for each, and possible common mechanisms, are poorly understood. The prevalence of RA is approximately 1% worldwide (148), whereas JRA has a lower prevalence among European populations, reportedly between 0.04% in Spain (149) and 0.1% in Finland (150) and other European/North American populations (151). Concordance rates have been reported to be 15.4% in MZ twins and 3.6% in DZ twins (152), reflecting a genetic component that appears to require strong environmental factors for disease development, where the strongest single risk factor is smoking (153).
The HLA-DR4 allele has been shown to be the strongest genetic risk factor for RA (154). The B27 (155,156) and DR1 (154) alleles also appear to constitute risk alleles for RA development. Furthermore, there are suggestions that genes within the B8, DR3 haplotype also contribute to susceptibility to RA (18,155, 57159), including JRA (156). Other risk alleles for JRA include the DR5 (160), DR8 (161) and B35 (161) alleles, whereas the DR15 and DR4 alleles have been shown to be protective (161,162). In addition to the HLA locus, over 30 genetic loci have been associated with risk for RA, many of which have been identified in recent years. RA was initially reported to be associated with PTPN22 in Caucasians (163) and peptidyl arginine deiminase, type IV (PADI4) in Asian patients (164). Other genes found to be associated with RA by GWAS include tumor necrosis factor receptor–associated factor 1 and encoding complement component 5 (TRAF1-C5); STAT4; TNFAIP3; IL2-IL21; CD40; IL2RA; protein tyrosine phosphatase, receptor type, C (PTPRC) and IRF5 (reviewed in [165]), where CTLA4 was associated with both RA and JRA (166). Other genes associated with JRA include TNFα, macrophage migration inhibitory factor (MIF) and IL-6 (reviewed in [167]).
Studies on RA and JRA contain a total of 5,724 individuals, of whom 74 were IgAD (1:77). In JRA, 55 of 2,030 patients were IgAD (1:37), whereas in RA, 19 of 3,694 patients were IgAD (1:194) (Table 6). It is therefore likely that the increase in IgAD in rheumatic diseases is accountable to large increases in its frequency in JRA, with only a trend for a higher prevalence in RA patients.
Table 6
Table 6
Prevalence of IgA deficiency among JRA and RA patients.
A common genetic background for selected autoimmune disorders, such as GD, SLE, T1D, CD and potentially MG and RA, involving both MHC and non-MHC encoded genes, has previously been suggested (14,168). There is also a considerable overlap in concomitant diseases; for example, T1D is prevalent in patients with GD, SLE, CD and RA. Furthermore, CD is overrepresented in patients with GD (168), and patients with SLE also show a higher prevalence of thyroid disorders (169,170). In this report, we have added IgAD to this group of diseases, since it shows a markedly increased prevalence in GD, SLE, T1D and CD (Table 7).
Table 7
Table 7
Overlap between immune-mediated diseases.
IgAD is thought to be present from birth in most cases. Theoretically, the increased frequency of infections associated with IgAD could therefore precipitate autoimmune disorders such as GD and SLE. However, in CD, IgAD has occasionally been reported to occur after the onset of the gastrointestinal symptoms. Thus, the common genetic background is likely to be the main contributor to the different autoimmune disorders where environmental factors determine if, and when, the primary and subsequent diseases will appear.
The gene(s) involved are primarily located within the MHC region, where the population-attributable risk is strong in T1D, CD and RA and moderate in GD and SLE (168). Our recent preliminary work in IgAD, based on 100 multicase families, suggests a similarly strong MHC-associated risk in these patients. However, owing to strong linkage disequilibrium within the MHC region, the gene(s) involved in disease pathogenesis, with the possible exception of HLA-DQ in CD, have not yet been identified.
It is well documented that IgAD is strongly associated with the MHC region, in particular, the HLA-B8, DR3, DQ2 haplotype (9). This haplotype is also associated with GD, SLE, T1D and CD (reviewed in [16,171]). Although single loci within the MHC region were initially thought to confer susceptibility or resistance to different autoimmune diseases, the current picture is markedly more complex, since multiple loci/genes have been shown to confer independent risk both in SLE (12,51,172) and T1D (91,92,173,174) (Figure 1). This also appears to be true for IgAD where genes both within the class II (9,175) and class III region (176178) have been shown to be associated with the defect (Figure 1). Multiple loci have also been suggested to be involved in MG (17), another 8.1 haplotype–associated disease, as well as immune-mediated diseases associated with other HLA haplotypes, including multiple sclerosis (MS) (179) and RA (18,159,175,180).
Figure 1
Figure 1
Markers across the HLA region associated with risk and protection to IgAD and selected autoimmune disorders. The HLA-DRB1*1501 allele constitutes a risk factor for SLE, but is a protective factor for IgAD and T1D.
Case-control studies in European SLE patients have shown a consistent association with the HLA-DRB1*1501 allele and its linked haplotypes (45,46). An association with the DRB1*1501 allele (rs3135391 serving as a tagging SNP) has also been observed in patients with MS (12). Although a few case reports on IgAD in MS patients have been published, no large-scale screening studies have been performed to date. In view of the almost complete protection against IgAD by the DRB1*1501 allele (12), its frequency among MS patients would be expected to be quite low. Similarly, the DRB1*1501-DQB1*0602 haplotype confers protection from T1D (181). Thus, the same allele confers risk or protection in different immune-mediated diseases, suggesting its involvement at a crucial step in pathogenesis.
The association between a given disease and the MHC could either be due to coding mutations/variations in a given gene, directly influencing its function, or, alternatively, mutations/variations in regulatory sequences, affecting the expression of the gene. Examples of the former include copy number variation of functional C4 alleles in SLE (46) and potentially IgAD (182) and promoter polymorphisms in nuclear factor of kappa light polypeptide gene enhancer in B-cells inhibitor-like 1 (NFKBIL1, also known as IKBL) (183), DEAD (Asp-Glu-Ala-Asp) box polypeptide 39B (DDX39B, also known as BAT1) (184) and HLA-DQA1 (185) in the latter.
We previously suggested that an IgAD predisposing (mutated/variant) haplotype (B8, DR3, DQ2) is present at a frequency of 0.46% in the general Swedish population (10). Preliminary experiments have indeed shown multiple sequence differences between patients and controls homozygous for the 8.1 haplotype. Similar findings have previously been reported by Yan et al. (186) in Alaskan natives with RA, where multiple mutations/variations were identified in the disease-associated haplotype. The presence of such a predisposing haplotype may explain the overlap in HLA between IgAD and autoimmunity, since the affected variant of the 8.1 haplotype might constitute a risk factor for developing additional disorders, including GD, SLE, T1D, CD and potentially MG and RA. However, additional studies in cohorts of patients with different auto-immune diseases will be necessary to substantiate this notion, and full sequencing of the MHC region of the 8.1 haplotype may ultimately be required to identify the potential mutations/variants involved.
The mechanism underlying the induction of IgAD still remains elusive. It is however likely that the pathophysiological process involves a break of tolerance against IgA itself (since 30% of IgAD patients have demonstrable titers of IgG antibodies against IgA) or one of the factors involved in the switching process (such as a proliferation-inducing ligand [APRIL] or B-cell activating factor [BAFF]).
A number of non-MHC genes have also been shown to be associated with GD, SLE, T1D and CD. These genes generally cluster into pathways involved in T-cell differentiation, cell activation/signaling and innate immunity and have been shown to be associated with single or several diseases (Table 8). It is however noteworthy that there is also a lack of association of given “autoimmune” genes such as PTPN22, which shows association with a large number of diseases, including some of the above disorders, suggesting differences in the pathophysiological pathways.
Table 8
Table 8
SNPs reported to be associated with IgAD and selected autoimmune disorders.a
IFIH1 is located on chromosome 2q24 and encodes the interferon induced with helicase C domain 1 protein. Together with retinoic acid-inducible gene I (RIG-1), it functions as a sensor for viral infections. IFIH1 expression is highly upregulated in activated immune cells in response to type 1 interferon induced by viral infections, suggesting that it could potentially be involved in the pathogenesis of autoimmune diseases including T1D (187). Several SNPs within the IFIH1 gene and its 3′ untranslated region show an association with T1D (rs2111485, rs13422767, rs1990760 and rs3747517) (188), where the rs1990760 marker (Ala946Thr) is the most strongly associated (reviewed in [189]). Most of these rare IFIH1 alleles are protective against disease (190).
A recent large-scale study also showed a highly significant association of rs1990760 to SLE in Caucasian (191) but not in Japanese patients (192). Moreover, GD has also been shown to be associated with rs1990760 (193), although this point remains controversial (194196). CD, on the other hand, does not appear to be associated with rs1990760 (74).
In 2010, we performed a GWAS on a large cohort of patients with IgAD (13) and identified an association with rs1990760 in the IFIH1 gene. Taken together, there is thus ample evidence for the implication of IFIH1 both in IgAD and in several autoimmune disorders, although the mechanism involved remains elusive.
CLEC16A, located on chromosome 16p13, is widely expressed on B lymphocytes, natural killer and dendritic cells (197). Several SNPs (rs2903692, rs17673553, rs725613 and rs12708716) within the CLEC16A gene have been shown to be associated with T1D in different populations (196,198203). Dubois et al. (204) recently also identified an association between the class II, major histocompatibility complex, transactivator (CIITA)–suppressor of cytokine signaling 1 (SOCS1)-CLEC16A region and CD, although it just reached borderline genome-wide significance. Another study, however, suggested that CLEC16A (rs2903692) is not involved in susceptibility to CD development (205). rs12708716 was also suggested to be associated with SLE (191) where the A allele confers susceptibility. Awata et al., on the other hand, showed that rs2903692 was not associated with GD in Japanese patients (206). In IgAD, we recently showed suggestive evidence for association with CLEC16A (rs6498142 and rs7201845) (13), again suggesting a common genetic link.
One remaining question is whether the MHC- and non-MHC–associated susceptibility genes are acting independently or synergistically in the pathophysiological processes underlying auto-immune diseases. A number of studies have addressed this question, and Hodge et al. (207) and Jacobson et al. (25) showed that interaction between HLA-DRB1*03 and different thyroglobulin variants conferred an increased risk for GD. A subsequent study in Japanese subjects (208) suggested that there was also an interaction between selected HLA-A and DP alleles and CTLA4 in a subgroup of GD patients, although Kula et al. (209) suggested that the interaction with CTLA4 was due to HLA-DR encoding genes.
In T1D, a study in Belgian patients showed no interaction between HLA-DQ and the IFIH1 rs1990760 SNP (210). However, PTPN22 Trp620 (rs2476601) has a higher relative risk in T1D patients carrying low-risk MHC class II genotypes (non-DR3/DR4) than in those carrying the high-risk ones, suggesting a potential interaction (211213). Moreover, a Norwegian study indicated a weak synergistic effect between FOXP3 and the HLA-DR3, DQ2, haplotype both in T1D and CD patients (214). A recent case-control collection study also showed a significant interaction between HLA-DR3 and IRF5 in patients with SLE (215). Similar interaction studies in IgAD have not yet been performed.
In summary, IgAD is markedly more prevalent in patients with a variety, albeit not all (such as MG [14]), of 8.1 haplotype–associated autoimmune diseases. Similarities in the genetic susceptibility suggest involvement of common pathophysiological pathways, implicating that IgAD, as recently suggested by Ferreira et al. (13), may in fact be an autoimmune disease. However, additional dense SNPing and sequencing of the implicated genes may be required to fully understand the mechanisms involved.
ACKNOWLEDGMENTS
This work was supported by the Swedish Research Council, the European Union–funded project EURO-PADnet (grant 201 549) and the KI funding for PhD students program for PhD students at the Karolinska Institutet (N Wang). We are indebted to Francesco Cucca at the University of Sassari, Italy, for providing samples from Italian patients with T1D and Magdalena Janzi and Ryan Ramanujam for their contributions in the early stages of this work.
Footnotes
Online address: http://www.molmed.org
DISCLOSURE
TW Behrens is a full-time employee of Genentech.
1. Pan-Hammarström Q, Hammarström L. Antibody deficiency diseases. Eur J Immunol. 2008;38:327–33. [PubMed]
2. Pereira LF, et al. Prevalence of selective IgA deficiency in Spain: more than we thought. Blood. 1997;90:893. [PubMed]
3. Kanoh T, et al. Selective IgA deficiency in Japanese blood donors: frequency and statistical analysis. Vox Sang. 1986;50:81–6. [PubMed]
4. Weber-Mzell D, et al. Gender, age and seasonal effects on IgA deficiency: a study of 7293 Caucasians. Eur J Clin Invest. 2004;34:224–8. [PubMed]
5. Janzi M, et al. Selective IgA deficiency in early life: association to infections and allergic diseases during childhood. Clin Immunol. 2009;133:78–85. [PubMed]
6. Notarangelo LD, et al. Primary immunodeficiencies: 2009 update. J Allergy Clin Immunol. 2009;124:1161–78. [PMC free article] [PubMed]
7. Latiff AHA, Kerr MA. The clinical significance of immunoglobulin A deficiency. Ann Clin Biochem. 2007;44:131–9. [PubMed]
8. Cunningham-Rundles C, Fotino M, Rosina O, Peter JB. Selective IgA deficiency, IgG subclass deficiency, and the major histocompatibility complex. Clin Immunol Immunopathol. 1991;61:S61–9. [PubMed]
9. Olerup O, Smith CI, Hammarström L. Different amino acids at position 57 of the HLA-DQ beta chain associated with susceptibility and resistance to IgA deficiency. Nature. 1990;347:289–90. [PubMed]
10. Mohammadi J, et al. IgA deficiency and the MHC: assessment of relative risk and micro-heterogeneity within the HLA A1 B8, DR3 (8.1) haplotype. J Clin Immunol. 2010;30:138–43. [PubMed]
11. MacHulla HK, et al. HLA-A, B, Cw and DRB1, DRB3/4/5, DQB1, DPB1 frequencies in German immunoglobulin A-deficient individuals. Scand J Immunol. 2000;52:207–11. [PubMed]
12. Goyette P, et al. Mapping of multiple susceptibility variants within the MHC region for 7 immune-mediated diseases. Proc Natl Acad Sci U S A. 2009;106:18680–5. [PubMed]
13. Ferreira RC, et al. Association of IFIH1 and other autoimmunity risk alleles with selective IgA deficiency. Nat Genet. 2010;42:777–80. [PubMed]
14. Ramanujam R, Piehl F, Pirskanen R, Gregersen PK, Hammarström L. Concomitant autoimmunity in myasthenia gravis: lack of association with IgA deficiency. J Neuroimmunol. 2011;236:118–22. [PMC free article] [PubMed]
15. Jorgensen GH, et al. Association of immunoglobulin A deficiency and elevated thyrotropin-receptor autoantibodies in two Nordic countries. Hum Immunol. 2011;72:166–72. [PubMed]
16. Price P, et al. The genetic basis for the association of the 8.1 ancestral haplotype (A1, B8, DR3) with multiple immunopathological diseases. Immunol Rev. 1999;167:257–74. [PubMed]
17. Vandiedonck C, et al. Pleiotropic effects of the 8.1 HLA haplotype in patients with autoimmune myasthenia gravis and thymus hyperplasia. Proc Natl Acad Sci U S A. 2004;101:15464–9. [PubMed]
18. Jawaheer D, et al. Dissecting the genetic complexity of the association between human leukocyte antigens and rheumatoid arthritis. Am J Hum Genet. 2002;71:585–94. [PubMed]
19. Jacobson DL, Gange SJ, Rose NR, Graham NM. Epidemiology and estimated population burden of selected autoimmune diseases in the United States. Clin Immunol Immunopathol. 1997;84:223–43. [PubMed]
20. Prabhakar BS, Bahn RS, Smith TJ. Current perspective on the pathogenesis of Graves’ disease and ophthalmopathy. Endocr Rev. 2003;24:802–35. [PubMed]
21. Zöphel K, Roggenbuck D, Schott M. Clinical review about TRAb assay’s history. Autoimmun Rev. 2010;9:695–700. [PubMed]
22. Lantz M, Abraham-Nordling M, Svensson J, Wallin G, Hallengren B. Immigration and the incidence of Graves’ thyrotoxicosis, thyrotoxic multinodular goiter and solitary toxic adenoma. Eur J Endocrinol. 2009;160:201–6. [PubMed]
23. Wong GW, Cheng PS. Increasing incidence of childhood Graves’ disease in Hong Kong: a follow-up study. Clin Endocrinol (Oxf) 2001;54:547–50. [PubMed]
24. Tomer Y, Davies TF. Searching for the auto-immune thyroid disease susceptibility genes: from gene mapping to gene function. Endocr Rev. 2003;24:694–717. [PubMed]
25. Jacobson EM, Huber A, Tomer Y. The HLA gene complex in thyroid autoimmunity: from epidemiology to etiology. J Autoimmun. 2008;30:58–62. [PMC free article] [PubMed]
26. Farid NR, Stone E, Johnson G. Graves’ disease and HLA: clinical and epidemiologic associations. Clin Endocrinol (Oxf) 1980;13:535–44. [PubMed]
27. Zamani M, Spaepen M, Bex M, Bouillon R, Cassiman JJ. Primary role of the HLA class II DRB1*0301 allele in Graves disease. Am J Med Genet. 2000;95:432–7. [PubMed]
28. Yanagawa T, et al. Human histocompatibility leukocyte antigen-DQA1*0501 allele associated with genetic susceptibility to Graves’ disease in a Caucasian population. J Clin Endocrinol Metab. 1993;76:1569–74. [PubMed]
29. Marga M, Denisova A, Sochnev A, Pirags V, Farid NR. Two HLA DRB 1 alleles confer independent genetic susceptibility to Graves disease: relevance of cross-population studies. Am J Med Genet. 2001;102:188–91. [PubMed]
30. Jacobson EM, Tomer Y. The genetic basis of thyroid autoimmunity. Thyroid. 2007;17:949–61. [PubMed]
31. Tomer Y. Genetic susceptibility to autoimmune thyroid disease: past, present, and future. Thyroid. 2010;20:715–25. [PMC free article] [PubMed]
32. Pariente EA, et al. Collagenous colitis, IgA deficiency, Basedow’s disease and atrophic gastritis [in French] Gastroenterol Clin Biol. 1985;9:738–41. [PubMed]
33. Mano T, Kawakubo A, Yamamoto M. Isolated IgA deficiency accompanied by autoimmune thyroid disease. Intern Med. 1992;31:1201–3. [PubMed]
34. Hoffman WH, Helman SW, Sekul E, Carroll JE, Vega RA. Lambert-Eaton Myasthenic syndrome in a child with an autoimmune phenotype. Am. J. Med. Genet. A. 2003;119A:77–80. [PubMed]
35. Silva JM, de A, Silva CP, Melo FF, Silva LAA, Utagawa CY. Graves disease and IgA deficiency as manifestations of 22q11.2 deletion syndrome [in Portuguese] Arq Bras Endocrinol Metabol. 2010;54:572–7. [PubMed]
36. Ch’ng CL, Biswas M, Benton A, Jones MK, Kingham JGC. Prospective screening for coeliac disease in patients with Graves’ hyperthyroidism using anti-gliadin and tissue transglutaminase antibodies. Clin Endocrinol (Oxf) 2005;62:303–6. [PubMed]
37. Collin P, Salmi J, Hällström O, Reunala T, Pasternack A. Autoimmune thyroid disorders and coeliac disease. Eur J Endocrinol. 1994;130:137–40. [PubMed]
38. Cuoco L, et al. Prevalence and early diagnosis of coeliac disease in autoimmune thyroid disorders. Ital J Gastroenterol Hepatol. 1999;31:283–7. [PubMed]
39. Carroccio A, et al. Evidence of transient IgA anti-endomysial antibody positivity in a patient with Graves’ disease. Digestion. 1999;60:86–8. [PubMed]
40. Han J-W, et al. Genome-wide association study in a Chinese Han population identifies nine new susceptibility loci for systemic lupus erythematosus. Nat Genet. 2009;41:1234–7. [PubMed]
41. Ståhl-Hallengren C, Jönsen A, Nived O, Sturfelt G. Incidence studies of systemic lupus erythematosus in Southern Sweden: increasing age, decreasing frequency of renal manifestations and good prognosis. J Rheumatol. 2000;27:685–91. [PubMed]
42. Johnson AE, Gordon C, Palmer RG, Bacon PA. The prevalence and incidence of systemic lupus erythematosus in Birmingham, England: relationship to ethnicity and country of birth. Arthritis Rheum. 1995;38:551–8. [PubMed]
43. Alarcón-Segovia D, et al. Familial aggregation of systemic lupus erythematosus, rheumatoid arthritis, and other autoimmune diseases in 1,177 lupus patients from the GLADEL cohort. Arthritis Rheum. 2005;52:1138–47. [PubMed]
44. Deapen D, et al. A revised estimate of twin concordance in systemic lupus erythematosus. Arthritis Rheum. 1992;35:311–8. [PubMed]
45. Tsao BP. Update on human systemic lupus erythematosus genetics. Curr Opin Rheumatol. 2004;16:513–21. [PubMed]
46. Yang Y, et al. Gene copy-number variation and associated polymorphisms of complement component C4 in human systemic lupus erythematosus (SLE): low copy number is a risk factor for and high copy number is a protective factor against SLE susceptibility in European Americans. Am J Hum Genet. 2007;80:1037–54. [PubMed]
47. Hashimoto H, et al. HLA antigens associated with systemic lupus erythematosus in Japan. J Rheumatol. 1985;12:919–23. [PubMed]
48. Hirose S, Ogawa S, Nishimura H, Hashimoto H, Shirai T. Association of HLA-DR2/DR4 heterozygosity with systemic lupus erythematosus in Japanese patients. J Rheumatol. 1988;15:1489–92. [PubMed]
49. Hong GH, et al. Association of complement C4 and HLA-DR alleles with systemic lupus erythematosus in Koreans. J Rheumatol. 1994;21:442–7. [PubMed]
50. Harley JB, et al. Genome-wide association scan in women with systemic lupus erythematosus identifies susceptibility variants in ITGAM, PXK, KIAA1542 and other loci. Nat Genet. 2008;40:204–10. [PMC free article] [PubMed]
51. Fernando MMA, et al. Identification of two independent risk factors for lupus within the MHC in United Kingdom families. PLoS. Genet. 2007;3:e192. [PubMed]
52. Harley ITW, Kaufman KM, Langefeld CD, Harley JB, Kelly JA. Genetic susceptibility to SLE: new insights from fine mapping and genome-wide association studies. Nat Rev Genet. 2009;10:285–90. [PMC free article] [PubMed]
53. Cassidy JT, Burt A, Petty R, Sullivan D. Selective IgA deficiency in connective tissue diseases. N Engl J Med. 1969;280:275. [PubMed]
54. Alarcón-Segovia D, Fishbein E. Serum immunoglobulins in systemic lupus erythematosus. Clin Sci. 1972;43:121–31. [PubMed]
55. Gershwin ME, Blaese RM, Steinberg AD, Wistar R, Jr, Strober W. Antibodies to nucleic acids in congenital immune deficiency states. J Pediatr. 1976;89:377–81. [PubMed]
56. Yewdall V, et al. Systemic lupus erythematosus and IgA deficiency. J Clin Lab Immunol. 1983;10:13–8. [PubMed]
57. Kuştimur S, Gülmezoğlu E. Selective IgA deficiency in patients with systemic lupus erythematosus and rheumatoid arthritis [in Turkish] Mikrobiyol Bul. 1985;19:190–9. [PubMed]
58. Rifle G, et al. Selective IgA deficiency and systemic lupus erythematosus. Ann Med Interne (Paris) 1988;139:134–7. [PubMed]
59. Calabozo Raluy M, Gamir Gamir ML, Medina Luezas J, Díaz-Migu el Pérez C, Alonso Ruiz A. Selective deficiency of IgA in autoimmune diseases [in Spanish] Rev Clin Esp. 1990;186:163–5. [PubMed]
60. Kaufman LD, Heinicke MH, Hamburger M, Gorevic PD. Male lupus: prevalence of IgA deficiency, 7S IgM and abnormalities of reticuloendothelial system Fc-receptor function. Clin Exp Rheumatol. 1991;9:265–9. [PubMed]
61. Rankin EC, Isenberg DA. IgA deficiency and SLE: prevalence in a clinic population and a review of the literature. Lupus. 1997;6:390–4. [PubMed]
62. Cassidy JT, Kitson RK, Selby CL. Selective IgA deficiency in children and adults with systemic lupus erythematosus. Lupus. 2007;16:647–50. [PubMed]
63. Mantovani APF, Monclaro MP, Skare TL. Prevalence of IgA deficiency in adult systemic lupus erythematosus and the study of the association with its clinical and autoantibody profiles. Rev Bras Reumatol. 2010;50:273–82. [PubMed]
64. Bachmann R. Studies on the serum gamma-A-globulin level. 3. The frequency of A-gamma-A-globulinemia. Scand J Clin Lab Invest. 1965;17:316–20. [PubMed]
65. Claman HN, Merrill DA, Peakman D, Robinson A. Isolated severe gamma A deficiency: immunoglobulin levels, clinical disorders, and chromosome studies. J Lab Clin Med. 1970;75:307–15. [PubMed]
66. Bach GL, Pillary VK, Kark RM. Immunoglobulin (IgA) deficiency in systemic lupus erythematosus: report of a case and family studies. Acta Rheumatol Scand. 1971;17:63–71. [PubMed]
67. Cleland LG, Bell DA. The occurrence of systemic lupus erythematosus in two kindreds in association with selective IGA deficiency. J Rheumatol. 1978;5:288–93. [PubMed]
68. Woo P, Pereira RS, Lever AM. Persistent immunoglobulin deficiency after prednisolone and antiepileptic therapy in a C2 deficient patient with lupus-like syndrome. J Rheumatol. 1984;11:828–31. [PubMed]
69. Katial RK, Hatch RM, Baker MR. Cardiac tamponade and recurrent upper respiratory tract infections in a 22-year-old woman. Ann Allergy. 1994;73:473–7. [PubMed]
70. Arai J, et al. Non-X-linked hyper-IgM syndrome with systemic lupus erythematosus. Clin Exp Rheumatol. 1998;16:84–6. [PubMed]
71. John M, Lam M, Latham B, Saker B, French MA. Nephrotic syndrome in a patient with IgA deficiency-associated mesangioproliferative glomerulonephritis. Pathology. 2000;32:56–8. [PubMed]
72. Desar IME, Weemaes CMR, van Deuren M, van der Meer JWM. Reversible hypogamma-globulinaemia. Neth J Med. 2007;65:381–5. [PubMed]
73. Feng L. Epidemiological study of selective IgA deficiency among 6 nationalities in China [in Chinese] Zhonghua Yi Xue Za Zhi. 1992;72:88–90. 128. [PubMed]
74. Smyth DJ, et al. Shared and distinct genetic variants in type 1 diabetes and celiac disease. N Engl J Med. 2008;359:2767–77. [PMC free article] [PubMed]
75. Karvonen M, Tuomilehto J, Libman I, LaPorte R. A review of the recent epidemiological data on the worldwide incidence of type 1 (insulin-dependent) diabetes mellitus. Diabetologia. Vol. 36. World Health Organization; 1993. DIAMOND Project Group; pp. 883–92. [PubMed]
76. EURODIAB ACE Study Group. Variation and trends in incidence of childhood diabetes in Europe. Lancet. 2000;355:873–6. [PubMed]
77. Onkamo P, Väänänen S, Karvonen M, Tuomilehto J. Worldwide increase in incidence of type I diabetes: the analysis of the data on published incidence trends. Diabetologia. 1999;42:1395–403. [PubMed]
78. DIAMOND Project Group. Incidence and trends of childhood type 1 diabetes worldwide 1990–1999. Diabet. Med. 2006;23:857–66. [PubMed]
79. Virtanen SM, Knip M. Nutritional risk predictors of beta cell autoimmunity and type 1 diabetes at a young age. Am J Clin Nutr. 2003;78:1053–67. [PubMed]
80. Bach J-F. The effect of infections on susceptibility to autoimmune and allergic diseases. N. Engl. J. Med. 2002;347:911–20. [PubMed]
81. Zipitis CS, Akobeng AK. Vitamin D supplementation in early childhood and risk of type 1 diabetes: a systematic review and meta-analysis. Arch Dis Child. 2008;93:512–7. [PubMed]
82. Kyvik KO, Green A, Beck-Nielsen H. Concordance rates of insulin dependent diabetes mellitus: a population based study of young Danish twins. BMJ. 1995;311:913–7. [PMC free article] [PubMed]
83. Redondo MJ, et al. Heterogeneity of type I diabetes: analysis of monozygotic twins in Great Britain and the United States. Diabetologia. 2001;44:354–62. [PubMed]
84. Hyttinen V, Kaprio J, Kinnunen L, Koskenvuo M, Tuomilehto J. Genetic liability of type 1 diabetes and the onset age among 22,650 young Finnish twin pairs: a nationwide follow-up study. Diabetes. 2003;52:1052–5. [PubMed]
85. Condon J, et al. A study of diabetes mellitus within a large sample of Australian twins. Twin Res Hum Genet. 2008;11:28–40. [PubMed]
86. Redondo MJ, Jeffrey J, Fain PR, Eisenbarth GS, Orban T. Concordance for islet autoimmunity among monozygotic twins. N. Engl. J. Med. 2008;359:2849–50. [PubMed]
87. WHO Multinational Project for Childhood Diabetes Group. Familial insulin-dependent diabetes mellitus (IDDM) epidemiology: standardization of data for the DIAMOND Project. Bull World Health Organ. 1991;69:767–77. [PubMed]
88. Anaya J-M, et al. Familial clustering of autoimmune diseases in patients with type 1 diabetes mellitus. J Autoimmun. 2006;26:208–14. [PubMed]
89. Steenkiste A, et al. 14th International HLA and Immunogenetics Workshop: report on the HLA component of type 1 diabetes. Tissue Antigens. 2007;69(Suppl 1):214–25. [PubMed]
90. Noble JA, Valdes AM, Thomson G, Erlich HA. The HLA class II locus DPB1 can influence susceptibility to type 1 diabetes. Diabetes. 2000;49:121–5. [PubMed]
91. Howson JMM, Walker NM, Clayton D, Todd JA. Confirmation of HLA class II independent type 1 diabetes associations in the major histocompatibility complex including HLA-B and HLA-A. Diabetes Obes. Metab. 2009;11(Suppl 1):31–45. [PMC free article] [PubMed]
92. Valdes AM, Thomson G. Several loci in the HLA class III region are associated with T1D risk after adjusting for DRB1-DQB1. Diabetes Obes. Metab. 2009;11(Suppl 1):46–52. [PMC free article] [PubMed]
93. Pociot F, et al. Genetics of type 1 diabetes: what’s next? Diabetes. 2010;59:1561–71. [PMC free article] [PubMed]
94. Cerutti F, et al. Selective IgA deficiency in juvenile-onset insulin-dependent diabetes mellitus [in Italian] Pediatr Med Chir. 1988;10:197–201. [PubMed]
95. Liblau RS, Caillat-Zucman S, Fischer AM, Bach JF, Boitard C. The prevalence of selective IgA deficiency in type 1 diabetes mellitus. APMIS. 1992;100:709–12. [PubMed]
96. Smith WI, Rabin BS, Huellmantel A, Van Thiel DH, Drash A. Immunopathology of juvenile-onset diabetes mellitus. I. IgA deficiency and juvenile diabetes. Diabetes. 1978;27:1092–7. [PubMed]
97. Fraser-Reynolds KA, Butzner JD, Stephure DK, Trussell RA, Scott RB. Use of immunoglobulin A-antiendomysial antibody to screen for celiac disease in North American children with type 1 diabetes. Diabetes Care. 1998;21:1985–9. [PubMed]
98. Picarelli A, et al. Anti-endomysial antibody of IgG1 isotype detection strongly increases the prevalence of coeliac disease in patients affected by type I diabetes mellitus. Clin Exp Immunol. 2005;142:111–5. [PubMed]
99. Ferguson A, MacDonald TT, McClure JP, Holden RJ. Cell-mediated immunity to gliadin within the small-intestinal mucosa in coeliac disease. Lancet. 1975;1:895–7. [PubMed]
100. Bingley PJ, et al. Undiagnosed coeliac disease at age seven: population based prospective birth cohort study. BMJ. 2004;328:322–3. [PMC free article] [PubMed]
101. Fasano A, et al. Prevalence of celiac disease in at-risk and not-at-risk groups in the United States: a large multicenter study. Arch Intern Med. 2003;163:286–92. [PubMed]
102. Mäki M, et al. Prevalence of celiac disease among children in Finland. N Engl J Med. 2003;348:2517–24. [PubMed]
103. Tatar G, et al. Screening of tissue transglutaminase antibody in healthy blood donors for celiac disease screening in the Turkish population. Dig Dis Sci. 2004;49:1479–84. [PubMed]
104. West J, et al. Seroprevalence, correlates, and characteristics of undetected coeliac disease in England. Gut. 2003;52:960–5. [PMC free article] [PubMed]
105. Catassi C, et al. Why is coeliac disease endemic in the people of the Sahara? Lancet. 1999;354:647–8. [PubMed]
106. Cummins AG, Roberts-Thomson IC. Prevalence of celiac disease in the Asia-Pacific region. J Gastroenterol Hepatol. 2009;24:1347–51. [PubMed]
107. Mustalahti K, et al. The prevalence of celiac disease in Europe: results of a centralized, international mass screening project. Ann Med. 2010;42:587–95. [PubMed]
108. Greco L, et al. The first large population based twin study of coeliac disease. Gut. 2002;50:624–8. [PMC free article] [PubMed]
109. Nisticò L, et al. Concordance, disease progression, and heritability of coeliac disease in Italian twins. Gut. 2006;55:803–8. [PMC free article] [PubMed]
110. Liu E, Rewers M, Eisenbarth GS. Genetic testing: who should do the testing and what is the role of genetic testing in the setting of celiac disease? Gastroenterology. 2005;128:S33–7. [PubMed]
111. Petronzelli F, et al. Genetic contribution of the HLA region to the familial clustering of coeliac disease. Ann Hum Genet. 1997;61:307–17. [PubMed]
112. Trynka G, Wijmenga C, van Heel DA. A genetic perspective on coeliac disease. Trends Mol Med. 2010;16:537–50. [PubMed]
113. Lavö B, Knutson F, Knutson L, Sjöberg O, Hällgren R. Jejunal secretion of secretory immunoglobulins and gliadin antibodies in celiac disease. Dig Dis Sci. 1992;37:53–9. [PubMed]
114. Heneghan MA, Stevens FM, Cryan EM, Warner RH, McCarthy CF. Celiac sprue and immunodeficiency states: a 25-year review. J Clin Gastroenterol. 1997;25:421–5. [PubMed]
115. Cataldo F, Marino V, Ventura A, Bottaro G, Corazza GR. Prevalence and clinical features of selective immunoglobulin A deficiency in coeliac disease: an Italian multicentre study. Italian Society of Paediatric Gastroenterology and Hepatology (SIGEP) and “Club del Tenue” Working Groups on Coeliac Disease. Gut. 1998;42:362–5. [PMC free article] [PubMed]
116. Demir H, Yüce A, Koçak N, Ozen H, Gürakan F. Celiac disease in Turkish children: presentation of 104 cases. Pediatr Int. 2000;42:483–7. [PubMed]
117. Cataldo F, Marino V, Bottaro G, Greco P, Ventura A. Celiac disease and selective immunoglobulin A deficiency. J Pediatr. 1997;131:306–8. [PubMed]
118. McGowan KE, Lyon ME, Butzner JD. Celiac disease and IgA deficiency: complications of serological testing approaches encountered in the clinic. Clin Chem. 2008;54:1203–9. [PubMed]
119. Klemola T. Deficiency of immunoglobulin A. Ann Clin Res. 1987;19:248–57. [PubMed]
120. Collin P, et al. Selective IgA deficiency and coeliac disease. Scand J Gastroenterol. 1992;27:367–71. [PubMed]
121. Meini A, et al. Prevalence and diagnosis of celiac disease in IgA-deficient children. Ann Allergy Asthma Immunol. 1996;77:333–6. [PubMed]
122. Prince HE, Norman GL, Binder WL. Immunoglobulin A (IgA) deficiency and alternative celiac disease-associated antibodies in sera submitted to a reference laboratory for endomysial IgA testing. Clin Diagn Lab Immunol. 2000;7:192–6. [PMC free article] [PubMed]
123. Lenhardt A, et al. Role of human-tissue transglutaminase IgG and anti-gliadin IgG antibodies in the diagnosis of coeliac disease in patients with selective immunoglobulin A deficiency. Dig Liver Dis. 2004;36:730–4. [PubMed]
124. Sinclair D, Saas M, Turk A, Goble M, Kerr D. Do we need to measure total serum IgA to exclude IgA deficiency in coeliac disease? J Clin Pathol. 2006;59:736–9. [PMC free article] [PubMed]
125. Bilbao JR, et al. Immunoglobulin G autoantibodies against tissue-transglutaminase: a sensitive, cost-effective assay for the screening of celiac disease. Autoimmunity. 2002;35:255–9. [PubMed]
126. Martín-Pagola A, et al. Two-year follow-up of anti-transglutaminase autoantibodies among celiac children on gluten-free diet: comparison of IgG and IgA. Autoimmunity. 2007;40:117–21. [PubMed]
127. Bansal AK, Lindemann MJ, Ramsperger V, Kumar V. Celiac G+ antibody assay for the detection of autoantibodies in celiac disease. Ann N Y Acad Sci. 2009;1173:36–40. [PubMed]
128. Korponay-Szabó IR, et al. Elevation of IgG antibodies against tissue transglutaminase as a diagnostic tool for coeliac disease in selective IgA deficiency. Gut. 2003;52:1567–71. [PMC free article] [PubMed]
129. Drachman DB. Myasthenia gravis. N Engl J Med. 1994;330:1797–810. [PubMed]
130. Hoch W, et al. Auto-antibodies to the receptor tyrosine kinase MuSK in patients with myasthenia gravis without acetylcholine receptor antibodies. Nat Med. 2001;7:365–8. [PubMed]
131. Vaiopoulos G, et al. The association of systemic lupus erythematosus and myasthenia gravis. Postgrad Med J. 1994;70:741–5. [PMC free article] [PubMed]
132. Bhinder S, Majithia V, Harisdangkul V. Myasthenia gravis and systemic lupus erythematosus: truly associated or coincidental: two case reports and review of the literature. Clin Rheumatol. 2006;25:555–6. [PubMed]
133. Hrycek A. Systemic lupus erythematosus and myasthenia gravis. Pol Arch Med Wewn. 2009;119:582–5. [PubMed]
134. Christensen PB, et al. Associated autoimmune diseases in myasthenia gravis: a population-based study. Acta Neurol Scand. 1995;91:192–5. [PubMed]
135. Sahay BM, Blendis LM, Greene R. Relation between myasthenia gravis and thyroid disease. Br Med J. 1965;1:762–5. [PMC free article] [PubMed]
136. Toth C, McDonald D, Oger J, Brownell K. Acetylcholine receptor antibodies in myasthenia gravis are associated with greater risk of diabetes and thyroid disease. Acta Neurol Scand. 2006;114:124–32. [PubMed]
137. Kanazawa M, Shimohata T, Tanaka K, Nishizawa M. Clinical features of patients with myasthenia gravis associated with autoimmune diseases. Eur J Neurol. 2007;14:1403–4. [PubMed]
138. Kalb B, Matell G, Pirskanen R, Lambe M. Epidemiology of myasthenia gravis: a population-based study in Stockholm, Sweden. Neuroepidemiology. 2002;21:221–5. [PubMed]
139. McGrogan A, Sneddon S, de Vries CS. The incidence of myasthenia gravis: a systematic literature review. Neuroepidemiology. 2010;34:171–83. [PubMed]
140. Ramanujam R, Pirskanen R, Ramanujam S, Hammarström L. Utilizing twins concordance rates to infer the predisposition to myasthenia gravis. Twin Res Hum Genet. 2011;14:129–36. [PubMed]
141. Pirskanen R, Tiilikainen A, Hokkanen E. Histocompatibility (HL-A) antigens associated with myasthenia gravis: a preliminary report. Ann Clin Res. 1972;4:304–6. [PubMed]
142. Kaakinen A, Pirskanen R, Tiilikainen A. LD antigens associated with HL-A8 and myasthenia gravis. Tissue Antigens. 1975;6:175–12. [PubMed]
143. Compston DA, Vincent A, Newsom-Davis J, Batchelor JR. Clinical, pathological, HLA antigen and immunological evidence for disease heterogeneity in myasthenia gravis. Brain. 1980;103:579–601. [PubMed]
144. Giraud M, et al. Linkage of HLA to myasthenia gravis and genetic heterogeneity depending on anti-titin antibodies. Neurology. 2001;57:1555–60. [PubMed]
145. Giraud M, Vandiedonck C, Garchon HJ. Genetic factors in autoimmune myasthenia gravis. Ann N Y Acad Sci. 2008;1132:180–92. [PubMed]
146. Arnett FC, et al. The American Rheumatism Association 1987 revised criteria for the classification of rheumatoid arthritis. Arthritis Rheum. 1988;31:315–24. [PubMed]
147. Isennock M, Grosel JM. Juvenile idiopathic arthritis: can you recognize this complex diagnosis? JAAPA. 2011;24:22–7. [PubMed]
148. Harris ED. Rheumatoid arthritis: pathophysiology and implications for therapy. N Engl J Med. 1990;322:1277–89. [PubMed]
149. Modesto C, et al. Incidence and prevalence of juvenile idiopathic arthritis in Catalonia (Spain) Scand J Rheumatol. 2010;39:472–9. [PubMed]
150. Andersson Gäre B. Juvenile arthritis: who gets it, where and when? A review of current data on incidence and prevalence. Clin Exp Rheumatol. 1999;17:367–74. [PubMed]
151. Phelan JD, Thompson SD, Glass DN. Susceptibility to JRA/JIA: complementing general autoimmune and arthritis traits. Genes Immun. 2006;7:1–10. [PubMed]
152. Silman AJ, et al. Twin concordance rates for rheumatoid arthritis: results from a nationwide study. Br J Rheumatol. 1993;32:903–7. [PubMed]
153. Källberg H, et al. Smoking is a major preventable risk factor for rheumatoid arthritis: estimations of risks after various exposures to cigarette smoke. Ann Rheum Dis. 2011;70:508–11. [PMC free article] [PubMed]
154. Roudier J. HLA-DRB1 genes and extraarticular rheumatoid arthritis. Arthritis Res Ther. 2006;8:103. [PMC free article] [PubMed]
155. El-Gabalawy HS, et al. Association of HLA alleles and clinical features in patients with synovitis of recent onset. Arthritis Rheum. 1999;42:1696–705. [PubMed]
156. Glass DN, Litvin DA. Heterogeneity of HLA associations in systemic onset juvenile rheumatoid arthritis. Arthritis Rheum. 1980;23:796–9. [PubMed]
157. Avila-Portillo LM, Vargas-Alarcón G, Andrade F, Alarcón-Segovia D, Granados J. Linkage disequilibrium of HLA-DR3 and HLA-DR4 with HLA-B alleles in Mexican patients with rheumatoid arthritis. Clin Exp Rheumatol. 1994;12:497–502. [PubMed]
158. Hajeer AH, Worthington J, Silman AJ, Ollier WE. Association of tumor necrosis factor microsatellite polymorphisms with HLA-DRB1*04-bearing haplotypes in rheumatoid arthritis patients. Arthritis Rheum. 1996;39:1109–14. [PubMed]
159. Lee H-S, et al. Several regions in the major histocompatibility complex confer risk for anti-CCP-antibody positive rheumatoid arthritis, independent of the DRB1 locus. Mol Med. 2008;14:293–300. [PMC free article] [PubMed]
160. Miller ML, et al. Inherited predisposition to iridocyclitis with juvenile rheumatoid arthritis: selectivity among HLA-DR5 haplotypes. Proc Natl Acad Sci U S A. 1984;81:3539–42. [PubMed]
161. Säilä H, et al. HLA and susceptibility to juvenile idiopathic arthritis: a study of affected sib-pairs in an isolated Finnish population. J Rheumatol. 2004;31:2281–5. [PubMed]
162. Hollenbach JA, et al. Juvenile idiopathic arthritis and HLA class I and class II interactions and age-at-onset effects. Arthritis Rheum. 2010;62:1781–91. [PMC free article] [PubMed]
163. Begovich AB, et al. A missense single-nucleotide polymorphism in a gene encoding a protein tyrosine phosphatase (PTPN22) is associated with rheumatoid arthritis. Am J Hum Genet. 2004;75:330–7. [PubMed]
164. Suzuki A, et al. Functional haplotypes of PADI4, encoding citrullinating enzyme peptidylarginine deiminase 4, are associated with rheumatoid arthritis. Nat Genet. 2003;34:395–402. [PubMed]
165. Gregersen PK. Susceptibility genes for rheumatoid arthritis: a rapidly expanding harvest. Bull NYU Hosp Jt Dis. 2010;68:179–82. [PubMed]
166. Miterski B, et al. Complex genetic predisposition in adult and juvenile rheumatoid arthritis. BMC Genet. 2004;5:2. [PMC free article] [PubMed]
167. Prahalad S. Genetics of juvenile idiopathic arthritis: an update. Curr Opin Rheumatol. 2004;16:588–94. [PubMed]
168. Zhernakova A, van Diemen CC, Wijmenga C. Detecting shared pathogenesis from the shared genetics of immune-related diseases. Nat Rev Genet. 2009;10:43–55. [PubMed]
169. Appenzeller S, Pallone AT, Natalin RA, Costal-lat LTL. Prevalence of thyroid dysfunction in systemic lupus erythematosus. J Clin Rheumatol. 2009;15:117–9. [PubMed]
170. Antonelli A, et al. Prevalence of thyroid dysfunctions in systemic lupus erythematosus. Metab Clin Exp. 2010;59:896–900. [PubMed]
171. Candore G, Lio D, Colonna Romano G, Caruso C. Pathogenesis of autoimmune diseases associated with 8.1 ancestral haplotype: effect of multiple gene interactions. Autoimmun Rev. 2002;1:29–35. [PubMed]
172. Barcellos LF, et al. High-density SNP screening of the major histocompatibility complex in systemic lupus erythematosus demonstrates strong evidence for independent susceptibility regions. PLoS. Genet. 2009;5:e1000696. [PMC free article] [PubMed]
173. Eike MC, Becker T, Humphreys K, Olsson M, Lie BA. Conditional analyses on the T1DGC MHC dataset: novel associations with type 1 diabetes around HLA-G and confirmation of HLA-B. Genes Immun. 2009;10:56–67. [PubMed]
174. Cheung YH, Watkinson J, Anastassiou D. Conditional meta-analysis stratifying on detailed HLA genotypes identifies a novel type 1 diabetes locus around TCF19 in the MHC. Hum Genet. 2011;129:161–76. [PMC free article] [PubMed]
175. Fernando MMA, et al. Defining the role of the MHC in autoimmunity: a review and pooled analysis. PLoS. Genet. 2008;4:e1000024. [PMC free article] [PubMed]
176. Cucca F, et al. Evaluation of IgA deficiency in Sardinians indicates a susceptibility gene is encoded within the HLA class III region. Clin Exp Immunol. 1998;111:76–80. [PubMed]
177. Schroeder HW, Jr, et al. Susceptibility locus for IgA deficiency and common variable immunodeficiency in the HLA-DR3, -B8, -A1 haplotypes. Mol Med. 1998;4:72–86. [PMC free article] [PubMed]
178. De la Concha EG, et al. MHC susceptibility genes to IgA deficiency are located in different regions on different HLA haplotypes. J Immunol. 2002;169:4637–43. [PubMed]
179. Cree BAC, et al. A major histocompatibility class I locus contributes to multiple sclerosis susceptibility independently from HLA-DRB1*15:01. PLoS ONE. 2010;5:e11296. [PMC free article] [PubMed]
180. Vignal C, et al. Genetic association of the major histocompatibility complex with rheumatoid arthritis implicates two non-DRB1 loci. Arthritis Rheum. 2009;60:53–62. [PubMed]
181. Steck AK, Rewers MJ. Genetics of type 1 diabetes. Clin Chem. 2011;57:176–85. [PubMed]
182. Bu_in D, Truedsson L, Hammarström L, Smith CI, Sjöholm AG. C4 polymorphism and major histocompatibility complex haplotypes in IgA deficiency: association with C4A null haplotypes. Exp Clin Immunogenet. 1991;8:233–41. [PubMed]
183. Boodhoo A, et al. A promoter polymorphism in the central MHC gene, IKBL, influences the binding of transcription factors USF1 and E47 on disease-associated haplotypes. Gene Expr. 2004;12:1–11. [PubMed]
184. Price P, et al. Polymorphisms at positions −22 and −348 in the promoter of the BAT1 gene affect transcription and the binding of nuclear factors. Hum Mol Genet. 2004;13:967–74. [PubMed]
185. Morzycka-Wroblewska E, Munshi A, Ostermayer M, Harwood JI, Kagnoff MF. Differential expression of HLA-DQA1 alleles associated with promoter polymorphism. Immunogenetics. 1997;45:163–70. [PubMed]
186. Yan Z, et al. Resequencing of the human major histocompatibility complex in patients with rheumatoid arthritis and healthy controls in Alaska Natives of Southeast Alaska. Tissue Antigens. 2007;70:487–94. [PubMed]
187. Asahina Y, et al. Potential relevance of cytoplasmic viral sensors and related regulators involving innate immunity in antiviral response. Gastroenterology. 2008;134:1396–405. [PubMed]
188. Liu S, et al. IFIH1 polymorphisms are significantly associated with type 1 diabetes and IFIH1 gene expression in peripheral blood mononuclear cells. Hum Mol Genet. 2009;18:358–65. [PMC free article] [PubMed]
189. Chistiakov DA. Interferon induced with helicase C domain 1 (IFIH1) and virus-induced autoimmunity: a review. Viral Immunol. 2010;23:3–15. [PubMed]
190. Nejentsev S, Walker N, Riches D, Egholm M, Todd JA. Rare variants of IFIH1, a gene implicated in antiviral responses, protect against type 1 diabetes. Science. 2009;324:387–9. [PMC free article] [PubMed]
191. Gateva V, et al. A large-scale replication study identifies TNIP1, PRDM1, JAZF1, UHRF1BP1 and IL10 as risk loci for systemic lupus erythematosus. Nat Genet. 2009;41:1228–33. [PMC free article] [PubMed]
192. Gono T, et al. Interferon-induced helicase (IFIH1) polymorphism with systemic lupus erythematosus and dermatomyositis/polymyositis. Mod Rheumatol. 2010;20:466–70. [PubMed]
193. Sutherland A, et al. Genomic polymorphism at the interferon-induced helicase (IFIH1) locus contributes to Graves’ disease susceptibility. J Clin Endocrinol Metab. 2007;92:3338–41. [PubMed]
194. Zhao Z-F, et al. The A946T polymorphism in the interferon induced helicase gene does not confer susceptibility to Graves’ disease in Chinese population. Endocrine. 2007;32:143–7. [PubMed]
195. Penna-Martinez M, et al. The rs1990760 polymorphism within the IFIH1 locus is not associated with Graves’ disease, Hashimoto’s thyroiditis and Addison ’s disease. BMC Med Genet. 2009;10:126. [PMC free article] [PubMed]
196. Todd JA, et al. Robust associations of four new chromosome regions from genome-wide analyses of type 1 diabetes. Nat Genet. 2007;39:857–64. [PMC free article] [PubMed]
197. International Multiple Sclerosis Genetics Consortium (IMSGC) The expanding genetic overlap between multiple sclerosis and type I diabetes (2009) Genes Immun. 2009;10:11–4. [PMC free article] [PubMed]
198. Wellcome Trust Case Control Consortium. Genome-wide association study of 14,000 cases of seven common diseases and 3,000 shared controls. Nature. 2007;447:661–78. [PMC free article] [PubMed]
199. Hakonarson H, et al. A genome-wide association study identifies KIAA0350 as a type 1 diabetes gene. Nature. 2007;448:591–4. [PubMed]
200. Zoledziewska M, et al. Variation within the CLEC16A gene shows consistent disease association with both multiple sclerosis and type 1 diabetes in Sardinia. Genes Immun. 2009;10:15–7. [PubMed]
201. Wu X, et al. Intron polymorphism in the KIAA0350 gene is reproducibly associated with susceptibility to type 1 diabetes (T1D) in the Han Chinese population. Clin Endocrinol (Oxf) 2009;71:46–9. [PubMed]
202. Reddy MPL, et al. Association between type 1 diabetes and GWAS SNPs in the southeast US Caucasian population. Genes Immun. 2011;12:208–12. [PMC free article] [PubMed]
203. Martínez A, et al. Chromosomal region 16p13: further evidence of increased predisposition to immune diseases. Ann Rheum Dis. 2010;69:309–11. [PubMed]
204. Dubois PCA, et al. Multiple common variants for celiac disease influencing immune gene expression. Nat Genet. 2010;42:295–302. [PMC free article] [PubMed]
205. Dema B, et al. Autoimmune disease association signals in CIITA and KIAA0350 are not involved in celiac disease susceptibility. Tissue Antigens. 2009;73:326–9. [PubMed]
206. Awata T, et al. Association of type 1 diabetes with two loci on 12q13 and 16p13 and the influence coexisting thyroid autoimmunity in Japanese. J Clin Endocrinol Metab. 2009;94:231–5. [PubMed]
207. Hodge SE, et al. Possible interaction between HLA-DRbeta1 and thyroglobulin variants in Graves’ disease. Thyroid. 2006;16:351–5. [PubMed]
208. Takahashi M, Kimura A. HLA and CTLA4 polymorphisms may confer a synergistic risk in the susceptibility to Graves’ disease. J Hum Genet. 2010;55:323–6. [PubMed]
209. Kula D, et al. Interaction of HLA-DRB1 alleles with CTLA-4 in the predisposition to Graves’ disease: the impact of DRB1*07. Thyroid. 2006;16:447–53. [PubMed]
210. Aminkeng F, et al. IFIH1 gene polymorphisms in type 1 diabetes: genetic association analysis and genotype-phenotype correlation in the Belgian population. Hum Immunol. 2009;70:706–10. [PubMed]
211. Smyth DJ, et al. PTPN22 Trp620 explains the association of chromosome 1p13 with type 1 diabetes and shows a statistical interaction with HLA class II genotypes. Diabetes. 2008;57:1730–7. [PubMed]
212. Steck AK, et al. Association of the PTPN22/LYP gene with type 1 diabetes. Pediatr Diabetes. 2006;7:274–8. [PubMed]
213. Hermann R, et al. Lymphoid tyrosine phosphatase (LYP/PTPN22) Arg620Trp variant regulates insulin autoimmunity and progression to type 1 diabetes. Diabetologia. 2006;49:1198–208. [PubMed]
214. Bjørnvold M, et al. FOXP3 polymorphisms in type 1 diabetes and coeliac disease. J Autoimmun. 2006;27:140–4. [PubMed]
215. Taylor KE, et al. Risk alleles for systemic lupus erythematosus in a large case-control collection and associations with clinical subphenotypes. PLoS. Genet. 2011;7:e1001311. [PMC free article] [PubMed]
216. Hoddinott S, Dornan J, Bear JC, Farid NR. Immunoglobulin levels, immunodeficiency and HLA in type 1 (insulin-dependent) diabetes mellitus. Diabetologia. 1982;23:326–9. [PubMed]
217. Bertrams J, Schoeps L, Baur MP, Luboldt W, van Loghem E. IgG and IgA heavy chain allotypes in type 1 diabetes. J Immunogenet. 1983;10:305–10. [PubMed]
218. Page SR, Lloyd CA, Hill PG, Peacock I, Holmes GK. The prevalence of coeliac disease in adult diabetes mellitus. QJM. 1994;87:631–7. [PubMed]
219. Acerini CL, et al. Coeliac disease in children and adolescents with IDDM: clinical characteristics and response to gluten-free diet. Diabet Med. 1998;15:38–44. [PubMed]
220. Schober E, et al. Screening by anti-endomysium antibody for celiac disease in diabetic children and adolescents in Austria. J Pediatr Gastroenterol Nutr. 2000;30:391–6. [PubMed]
221. Laadhar L, et al. Prevalence of celiac disease serological markers in Tunisian type 1 diabetic adults [in French] Ann Biol Clin (Paris) 2006;64:439–44. [PubMed]
222. Sayarifard F, et al. Evaluation of serum IgA levels in Iranian patients with type 1 diabetes mellitus. Acta Diabetol. 2010 2010 Apr 22; [Epub ahead of print] [PubMed]
223. Sardi J, Casellas F, de Torres I, Malagelada JR. Clinical relevance of immunoglobulin A deficiency in celiac disease [in Spanish] Med Clin (Barc) 2000;115:687–9. [PubMed]
224. Bundey S, Doniach D, Soothill JF. Immunological studies in patients with juvenile-onset myasthenia gravis and in their relatives. Clin Exp Immunol. 1972;11:321–32. [PubMed]
225. Lisak RP, Zweiman B. Serum immunogloblin levels in myasthenia gravis, polymyositis, and dermatomyositis. J Neurol Neurosurg Psychiatr. 1976;39:34–7. [PMC free article] [PubMed]
226. Bramis J, Sloane C, Papatestas A, Genkins G, Aufses A. Serum-IgA in myasthenia gravis. Lancet. 1976;307:1243–4. [PubMed]
227. Behan P, Simpson J, Behan WH. Decreased serum-IgA in myasthenia gravis. Lancet. 1976;307:593–4. [PubMed]
228. Liblau R, Fischer AM, Shapiro DE, Morel E, Bach JF. The frequency of selective IgA deficiency in myasthenia gravis. Neurology. 1992;42:516–8. [PubMed]
229. Bluestone R, Goldberg LS, Katz RM, Marchesano JM, Calabro JJ. Juvenile rheumatoid arthritis: a serologic survey of 200 consecutive patients. J Pediatr. 1970;77:98–102. [PubMed]
230. Panush RS, et al. Juvenile rheumatoid arthritis: cellular hypersensitivity and selective IgA deficiency. Clin Exp Immunol. 1972;10:103–15. [PubMed]
231. Salmi TT, Schmidt E, Laaksonen AL, Anttila R, Kouvalainen K. Levels of serum immunoglobulins in juvenile rheumatoid arthritis. Ann Clin Res. 1973;5:395–7. [PubMed]
232. Cassidy JT, Petty RE, Sullivan DB. Abnormalities in the distribution of serum immunoglobulin concentrations in juvenile rheumatoid arthritis. J Clin Invest. 1973;52:1931–6. [PMC free article] [PubMed]
233. Cassidy JT, Petty RE, Sullivan DB. Occurrence of selective iga deficiency in children with juvenile rheumatoid arthritis. Arthritis and Rheumatism. 1977;20:181–3.
234. Barkley DO, Hohermuth HJ, Howard A, Webster DB, Ansell BM. IgA deficiency in juvenile chronic polyarthritis. J Rheumatol. 1979;6:219–24. [PubMed]
235. Pelkonen P, Savilahti E, Mäkelä AL. Persistent and transient IgA deficiency in juvenile rheumatoid arthritis. Scand J Rheumatol. 1983;12:273–9. [PubMed]
236. Moradinejad MH, et al. Prevalence of IgA deficiency in children with juvenile rheumatoid arthritis. Iran J Allergy Asthma Immunol. 2011;10:35–40. [PubMed]
237. Natvig JB, Harboe M, Fausa O, Tveit A. Family studies in individuals with selective absence of gamma-A-globulin. Clin Exp Immunol. 1971;8:229–36. [PubMed]
238. Thakar YS, Chande C, Dhanvijay AG, Pande S, Saoji AM. Analysis of immunoglobulin deficiency cases: a five year study. Indian J Pathol Microbiol. 1997;40:309–13. [PubMed]
239. Badcock LJ, Clarke S, Jones PW, Dawes PT, Mattey DL. Abnormal IgA levels in patients with rheumatoid arthritis. Ann Rheum Dis. 2003;62:83–4. [PMC free article] [PubMed]
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