Autoimmunity in Primary Immunodeficiency Disorders: An Updated Review on Pathogenic and Clinical Implications

Abstract

During the last years, studies investigating the intriguing association between immunodeficiency and autoimmunity led to the discovery of new monogenic disorders, the improvement in the knowledge of the pathogenesis of autoimmunity, and the introduction of targeted treatments. Autoimmunity is observed with particular frequency in patients with primary antibody deficiencies, such as common variable immunodeficiency (CVID) and selective IgA deficiency, but combined immunodeficiency disorders (CIDs) and disorders of innate immunity have also been associated with autoimmunity. Among CIDs, the highest incidence of autoimmunity is described in patients with autoimmune polyendocrine syndrome 1, LRBA, and CTLA-4 deficiency, and in patients with STAT-related disorders. The pathogenesis of autoimmunity in patients with immunodeficiency is far to be fully elucidated. However, altered germ center reactions, impaired central and peripheral lymphocyte negative selection, uncontrolled lymphocyte proliferation, ineffective cytoskeletal function, innate immune defects, and defective clearance of the infectious agents play an important role. In this paper, we review the main immunodeficiencies associated with autoimmunity, focusing on the pathogenic mechanisms responsible for autoimmunity in each condition and on the therapeutic strategies. Moreover, we provide a diagnostic algorithm for the diagnosis of PIDs in patients with autoimmunity.

Keywords: 22q11.2 deletion syndrome; CTLA-4; Immune dysregulation; LRBA; X-linked agammaglobulinemia; activated phosphoinositide 3-kinase d syndrome; common variable immunodeficiency; complement deficiency; selective IgA deficiency; severe combined immunodeficiency.

Figure 1

Pathogenesis of autoimmunity in immunodeficiency disorders. Figure legend: 22q11.2DS: chromosome 22q11.2 deletion syndrome; APC: antigen-presenting cells; APDS: Activated phosphoinositide 3-kinase d syndrome; APS-1: Autoimmune polyendocrine syndrome 1; CTLA-4: Cytotoxic lymphocyte antigen 4; CVID: Common variable immunodeficiency; LRBA: LPS-responsive beige-like anchor protein; PI3K: Phosphoinositide 3-kinase; PKCD: protein kinase C δ deficiency; PKCδ: protein kinase C δ; RAG: Recombinase activating genes; SCID: severe combined immunodeficiency; STAT: Signal Transducers and Activator of Transcription; WAS: Wiskott-Aldrich syndrome; XLA: X-linked agammaglobulinemia.

Figure 2

Therapeutic strategies for autoimmunity in patients with PIDs. The figure shows the current therapeutic options for specific PIDs. The choice of the therapeutic strategy (immunosuppressive agents, biologic drugs, HSCT, gene therapy) depends on the clinical severity, comorbidities and also on the availability and physician’s experience. * In patients with refractory autoimmune cytopenia. APDS: Activated phosphoinositide 3-kinase d syndrome; APS-1: Autoimmune polyendocrine syndrome 1; CTLA-4: Cytotoxic lymphocyte antigen 4; CVID: Common variable immunodeficiency; HCQ: Hydroxychloroquine; HIGM: Hyper-IgM syndromes; HSCT: hematopoietic stem cell transplantation; JAK: Janus kinase; LRBA: LPS-responsive beige-like anchor protein; MMF: mycophenolate mofetil; PI3K: Phosphoinositide 3-kinase; PKCD: protein kinase C δ deficiency; SCID: severe combined immunodeficiency; sIgAD: selective IgA deficiency; STAT: Signal Transducers and Activator of Transcription; Tregs: regulatory T cells; WAS: Wiskott-Aldrich syndrome; XLA: X-linked agammaglobulinemia.

Figure 3

Diagnostic approach to autoimmunity in patients with suspect immunodeficiency. Figure legend: APDS: Activated phosphoinositide 3-kinase d syndrome; APS-1: Autoimmune polyendocrine syndrome 1; CTLA-4: Cytotoxic lymphocyte antigen 4; CVID: Common variable immunodeficiency; HIGM: Hyper-IgM syndrome; LRBA: LPS-responsive beige-like anchor protein; PKCD: protein kinase C δ deficiency; RALD: Ras-associated leukoproliferative disorder; SCID: severe combined immunodeficiency; sIgAD: Selective IgA deficiency; SLE: systemic lupus erythematosus; STAT: Signal Transducers and Activator of Transcription; WAS: Wiskott-Aldrich syndrome; XLA: X-linked agammaglobulinemia.