Patients with defects in humoral immunity can also suffer from autoimmune complications. Since autoantibody production is limited by the B cell defects in these patients, other mechanisms likely contribute. X-linked agammaglobulinemia (XLA or Bruton’s agammaglobulenemia) is due to mutations in Bruton’s tyrosine kinase, a signal transduction molecule essential for B cell maturation. Btk-deficient B cells do not differentiate into antibody-producing plasma cells, and patients have pan-hypogammaglobulinema. Clinical manifestations include recurrent bacterial sinopulmonary infections, eczema, and diarrhea. Interestingly, XLA patients have an elevated incidence of juvenile rheumatoid arthritis, aspetic polyarthritis, cytopenias, IBD, and dermatomyositis [24
]. Hyper-IgM (HIGM) is a primary immunodeficiency from a genetic defect in the CD40 ligand pathway (X-linked HIGM) or in other proteins required for immunoglobulin class switch recombination. (MIM #308230). Consequently, HIGM patients have selective IgG deficiency with normal or elevated IgM levels, and are prone to recurrent sinopulmonary and gastrointestinal infections. Autoimmunity has often been described in HIGM patient series. In a cohort of 56 X-linked HIGM patients, IBD was seen in 6%, seronegative arthritis in 11%, chronic neutropenia in 45% [25
]. In another study of 79 patients, 60% were found to have neutropenia, with anemia and thrombocytopenia in 15% and 4%, respectively [26
]. Parvovirus B19 infection was only detected in 4% of the patients raising the suspicion of an autoimmune etiology independent of known infections.
Primary immunodeficiencies affecting CD8 and Natural killer (NK) cell cytotoxicity such as perforin deficiency (MIM #603553) and Griscelli Syndrome (MIM #607624) are associated with development of the hemophagocytic syndrome HLH (Hemophagocytic lymphocytic histiocytosis). In HLH, abnormal activation of both lymphocytes and innate cells, especially macrophages, can lead to immune cell infiltration into a number of organs, including the bone marrow, which leads to the complication of aplastic anemia and other features [27
]. Another immunodeficiency associated with HLH is X-linked Immunoproliferative Syndrome (XLP1, MIM #308240), a disorder characterized by fulminant mononucleosis, lymphomas and other lymphoproliferative syndromes and dysgammaglobulinemias. XLP1 results from mutations in the gene encoding SAP, an adapter protein that transduces signals from SLAM family receptors [28
]. This family of cell surface molecules is important in mediating homotypic lymphocyte interactions that are necessary for CD8 T and NK cell-mediated killing of EBV-infected targets, for development of the NKT cell lineage, as well as for T:B cell interactions required for germinal center formation and long-term humoral immunity[28
]. Abnormal cytolytic activity towards EBV infected B cells is a hallmark of this disorder, and like other disorders with abnormal cytolytic activity, HLH-type complications, including development of aplastic anemia, can develop in a small percentage of patients. Other rare complications include lymphocytic vasculitis and other lymphocytic tissue infiltration, which have on occasion been treated successfully with steroids. Whether these features result from inappropriate lymphocyte interactions, a lack of NKT cells or other alterations in lymphocyte homeostasis (including abnormal cell death that is observed in this syndrome) is unknown. The only definitive treatment for XLP is bone marrow transplantation.
Common variable immunodeficiency (CVID) is a heterogeneous group of diseases characterized by defective antibody production and underlying T cell defects. About 10% of CVID cases have been linked to autosomal dominant mutations in the TNF-receptor family member TACI [30
]. Clinical manifestations include recurrent sinopulmonary and gastrointestinal infections, with chronic bronchiectasis. Autoimmune diseases, particularly chronic inflammatory bowel disease, autoimmune cytopenias such as thrombocytopenia and hemolytic anemia, and rheumatoid arthritis are common in patients with CVID [32
]. Interestingly, mice engineered to lack TACI have a partial deficiency in B cell class-switching, but also develop splenomegaly and accumulate B cells that hyper-produce immunoglobulins, reproducing some features of CVID. [34
Wiskott - Aldrich syndrome (WAS) is a single gene PID that affects many aspects of immune cell function and is associated with a remarkably high prevalence of autoimmunity, as high as 70% in retrospective cohorts [36
] with some patients developing multiple autoimmune manifestations. The mutated gene in WAS encodes a multidomain protein called Wiskott -Aldrich syndrome protein (WASp). WASp is expressed exclusively in cells of the hematopoietic lineage and is critical for cytoskeletal remodeling via actin polymerization. Its role in cell and organelle motility, immune cell polarization, immunological synapse formation and T cell receptor (TCR) signaling was found from studies in WAS patients and WASp deficient mice [38
]. WASP deficiency can affect NK and T cell cytolytic function and T cell help for B cells. WAS patients have reduced antibody responses to polysaccharide vaccines and increased susceptibility to a wide variety of bacterial, viral and fungal infections. Mast Cell, NK cell, platelet and neutrophil function are also affected in WAS [39
]. WASp deficient mice were found to develop immune-mediated colitis and other autoimmune manifestations[42
], but how WASp deficiency predisposes to autoimmunity remained obscure until recently.
WASp deficient T cells are defective in their production of Interleukin-2, a cytokine known to be required for survival of regulatory T cells. Several groups have recently investigated the role of WASp in the development and function of regulatory T cells, which are essential in the control of T-cell mediated autoimmunity [43
] Humblet-Baron et al. reported normal thymic development but compromised peripheral survival and function of WASp-deficient murine Tregs. Maillard et al. found decreased numbers of both thymic and peripheral Tregs along with impaired homing and suppressive function of the WASp-deficient Treg cells, partly resulting from deficient production of IL-2 and IL-10. Adriani et al. described defective Treg function in WASp deficient T cells from mice and humans and restoration of Treg function by addition of IL-2, reinforcing the concept that defective IL-2 production in WAS may compromise Treg function and lead to autoimmunity. Defective Treg function may not be the only mechanism contributing to autoimmunity in WAS. Our own work has also suggested a role for defective production of Fas Ligand, a TNF-family member that enforces self-tolerance through inducing apoptosis via its receptor (Fas/CD95) in the pathogenesis of autoimmunity in WAS (Nikolov et al, manuscript submitted). Defective clearance of apoptotic cells, which can contribute to autoimmunity, was also suggested to play a role in the pathogenesis of autoimmunity in WAS [46
]. These findings illustrate how even in a single-gene PID, multiple mechanisms may contribute to autoimmune complications.