Here, we present evidence of positive and negative associations between HLA-DQB1*
05 and *
06 alleles and risk of FL, respectively. These results confirm our previous findings of an association between FL risk and SNPs in the HLA-DRB1*
0501 extended haplotype. A recent study reported that HLA-DRB1*
0101 was associated with increased risk for FL, whereas HLA-DRB1*
13 was inversely associated with FL risk14
. These alleles are in strong LD with HLA-DQB1*
0501 and HLA-DQB1*
06, respectively. Thus, our results highlight the need for further studies to determine whether HLA-DQB1
alleles, or some other gene variant(s), are causal in the pathogenesis of FL. Due to extended LD in the HLA
region, a typing study of non-Europeans with different LD patterns will aid in differentiating disease association signals in HLA-DRB1
from those in HLA-DQB1
HLA alleles associated with disease risk may alter the presentation of specific antigens of autoimmune or infectious origin, and thereby influence the immune response. For example, with type-1 diabetes the significant association between HLA
class II alleles and disease risk15
is attributed to differential presentation of insulin by specific HLA
class II protein isoforms16,17
. This, in turn, effects T-cell mediated destruction of insulin-secreting pancreatic β-cells. Similar models have been proposed to explain associations of HLA
alleles with narcolepsy, celiac disease, and rheumatoid arthritis17
. Although it is possible that FL pathogenesis is initiated by a similar mechanism dependent on a single antigen, a more generalized mechanism may be at play. Comparisons of the strength of associations between risk alleles and disease implicate a unique causal pathway for FL. In the cases of narcolepsy, celiac disease, and rheumatoid arthritis, >90% of patients are carriers of a risk allele17
. In contrast, 43% of FL cases in this study carried an HLA-DQB1*
05 allele. This implies a more subtle increase in risk per allele, or perhaps heterogeneity in the causal pathways in FL patients.
Changes in specific amino acids in HLA proteins are one reason that different immune systems may respond differently to the same antigen. Polymorphisms in the polypeptide binding groove can affect preference of the polypeptides to be presented to T-cells18
and thereby influence the immune response. For example, if we compare HLA-DQB1*
0501 and HLA-DQB1*
), seven amino acid changes are in pockets known to influence antigen binding or interaction with the T-cell receptor17–19
. If these amino acid changes affect the immune response to an antigen, it could conceivably influence susceptibility to FL via several mechanisms such as chronic immune activation, T-cell receptor stimulation or effects on HLA gene expression on antigen presenting cells.
Chronic immune activation is one proposed mechanism of lymphomagenesis that may explain the association of HLA
class II alleles with FL risk. B-cell proliferation is dependent on two signals, the first resulting from B-cell receptor interactions with antigen, and the second resulting from HLA class II-bound antigen-peptide interactions with T-cells20
. This two-part signal leads to clonal proliferation, class switch recombination and somatic hypermutation of B-cells. Chronic immune activation ensues when an autoantigen or a chronic infectious agent repeatedly provides growth signals to B-cells. Because class switch recombination and somatic hypermutation have been associated with DNA strand breaks, this process is potentially oncogenic and has been proposed as a mechanism of B-cell lymphomagenesis21
. The extent that a given antigen will cause chronic B-cell stimulation may be modified by the polymorphisms which define HLA class II alleles.
Interactions with regulatory T-cells (Tregs
) represent a second mechanism in which a differentially presented antigen could affect FL risk. B-cell NHL tumors contain high levels of Tregs
compared to control tissues, and these Tregs
suppress proliferation of tumor fighting CD4+ and CD8+ T-cells22,23
. Recent evidence indicates that T-helper cells can be converted to Tregs
by malignant FL B-cells in a process involving T-cell receptor stimulation24
. Because HLA class II molecules interact with the T-cell receptor, this suggests a role for HLA alleles in the generation of Tregs
. If an antigen, unique to FL, were differentially presented by the HLA
class II alleles, it could possibly affect Tregs
levels, thus modifying FL risk. The anti-apoptotic protein, BCL-2
, which is up-regulated in FL due to the t(14:18) translocation, may be a plausible candidate antigen that is unique for FL. Further studies will be needed to determine the potential role of Tregs
as a possible causal intermediate between HLA
class II alleles and FL risk.
FL immune evasion may also be caused by decreased HLA
class II protein expression. Decreased HLA class II protein expression has been linked to poor survival in DLBCL patients, likely the result of decreased immune surveillance25
. Additional research will be needed to assess the role of survival and HLA
class II expression in FL, and the role that HLA allelotypes play on expression of HLA
class II proteins.
In summary, this paper provides further evidence that HLA-DQB1*05 is associated with FL risk, and demonstrates a novel inverse association between HLA-DQB1*06 alleles and FL risk. Currently, it is unclear whether these HLA-DQB1 alleles are causal or merely markers of association. Here, we propose several mechanisms to support the biological plausibility of an association between HLA class II alleles with FL risk. Further genetic studies will be needed that include a large number of participants to provide in-depth coverage of the entire HLA class II region to elucidate the role of HLA alleles in the pathogenesis of FL.