Primary Immunodeficiency and Autoimmunity: Lessons From Human Diseases

Abstract

Primary immunodeficiency diseases (PID) are a genetically heterogenous group of >150 disorders that affect distinct components of the innate and adaptive immune system and are often associated with autoimmune diseases. We describe PID affecting T‐regulatory cells, complement and B cells or their products and discuss the possibility of a cause–effect relationship. The high concordance of T‐regulatory cell defects to organ‐specific autoimmune disease implies an obligatory role of these cells in maintaining tolerance to epithelial and endocrine tissues; the absence of central nervous system involvement may reflect immunological privilege. Congenital defects in C1q, C1r/s and C4 are strongly associated with systemic lupus erythematosus (SLE), and this pattern along with laboratory evidence suggests a major importance of classical pathway activity in safe elimination of immune complexes and prevention of immune complex disease (ICD). It is debatable whether this ICD is to be regarded as an autoimmune disease (resulting from a breakdown of immunological ignorance to antigens that are normally hidden), as autoantibodies may be absent, and tissue damage because of deposition of immune complexes could account for all of the pathology observed. Evidence for a causative link between primary antibody deficiencies and autoimmune disease is much less compelling and may in fact involve a common genetic background. However, arguments have also been made in favour of the notion that an intense antigen load as a result of recurrent or persistent infections may affect either tolerance or ignorance, e.g. by molecular mimicry or the presence of superantigens. Similar immunological mechanisms might account for the vast majority of autoimmune diseases.

Immunomodulation and lymphoma in humans

“…In particular, autoimmune disease is observed universally amongst patients with the T-cell deficiency disorders IPEX (immunodysregulation, polyendocrinopathy, enteropathy X-linked syndrome), APECED, and Omenn syndrome as a result of a deficiency in peripheral tolerance towards autoantigens mediated by regulatory T-cells (Arason et al, 2010). Recognition of this relationship between primary immunodeficiencies and autoimmunity is an important consideration as a driver of lymphoma risk, as described later in this review.…”

Celiac And Inflammatory Bowel Diseases In Children With Primary Humoral Immunodeficiency

“…The chronic sinusitis, LIP or bronchiectases are developing independently to regular substitution of IgG, even in higher dose [28]. The autoimmunity is associated with CVID in about 20-30% of patients and the hematological symptoms are most common [10,16,17,19,21,[29][30][31][32][33][34]. The dysregulation of immune system in CVID seemed to be paradoxical; while antibody production in response to pathogens and vaccines is impaired, at the same time the production autoantibodies might be excessive [32].…”

“…The autoimmune/inflammatory diseases of gastrointestinal tract (IBD) including Leśniowski-Crohn's disease, celiac disease, pernicious anemia, autoimmune liver disease, ulcerative colitis and nodular lymphoid hyperplasia (NLH) are the second group of complications (coexisting symptoms/diseases) noted in 20-50% of CVID patients [9,13,16,[18][19]21,[28][29][34][35][36]. The clinical symptoms of IBD in CVID are similar to patients without CVID but often more discrete, milder and unspecific.…”

Selective IgM Deficiency with T Cell Defects and Mycobacterium Avium Complex (MAC) Infection

“…Secondary selective IgM deficiency is often associated with malignancy or immunosuppressive therapy [6][7][8][9]. Selective IgM deficiency has been reported to be associated with autoimmunity and autoimmune diseases [10,11]; however, it remains unclear whether autoimmunity is primary or secondary to selective IgM deficiency, since patients with primary immunodeficiencies are more prone to autoimmunity and autoimmune diseases [12,13]. Furthermore, mice deficient in IgM develop spontaneous autoimmunity, including anti-DNA and immune complex nephritis [14], suggesting that autoimmunity may be secondary to selective IgM deficiency.…”