Autoimmunity as a continuum in primary immunodeficiency

Abstract

Purpose of review: Primary immunodeficiency disorders (PIDs) are no longer defined by infections alone. First clinical sign or sequelae of PID may include autoimmunity, such as cytopenias, arthritis or enteropathy. This review addresses the latest in multidisciplinary approaches for expanding clinical phenotypes of PIDs with autoimmunity, including new presentations of known entities and novel gene defects. We also discuss diagnostic tools for identifying the distinct changes in immune cells subsets and autoantibodies, mechanistic understanding of the process, and targeted treatment and indications for hematopoietic stem-cell transplantation (HSCT).

Recent findings: In the past years, increased awareness and use of genetic screening, confirmatory functional studies and immunological biomarkers opened the door for early recognition of PIDs among patients with autoimmunity. Large cohort studies detail the clinical spectrum and treatment outcome of PIDs with autoimmunity with specific immune genes (e.g., CTLA4, LRBA, PI3Kδ, NFKB1, RAG). The benefit of early recognition is initiation of targeted therapies with precise re-balancing of the dysregulated immune pathways (e.g., biologicals) or definitive therapy (e.g., HSCT).

Summary: Clinical presentation of patients with PID and autoimmunity is highly variable and requires in-depth diagnostics and precision medicine approaches.

FIGURE 1

Precision medicine therapy for the diverse disease spectrum of primary immunodeficiency (PID). The variable clinical presentation of PID is influenced by environmental triggers as wells as empirical therapy. For instance, rituximab therapy eliminates B cells and thus reduces autoantibodies but also increases risk of infections, whereas viral infections can stimulate dysregulated B cells and result in autoimmunity. The use of next-generation sequencing and functional immune studies can identify the precise molecular basis of disease and enable optimal treatment which targets the molecular defect and minimizes adverse effects.

Box 1

no caption available

FIGURE 2

The genetic basis for infections versus autoimmunity (AI) within PIDs. An inverse gradation of infectious and autoimmune complications exists for different primary immunodeficiencies. For example, SCID patients with complete RAG deficiency or loss of IL2RG function are plagued with infections but minimal autoimmunity whereas APECED have high autoimmunity but relatively few infections. Multiple primary immune dysregulation disorders (PIRD) can be caused by the same set of genetic mutations although particular mutations favor specific diseases such as FOXP3 mutations causing IPEX-like disorder. ∗Other endocrinopathies include Addison's disease, type 1 diabetes mellitus, adrenal corticotropic hormone insufficiency, and growth hormone deficiency. COMP, complement defects; ADA1/2, adenosine deaminase 1 and 2; AIC, autoimmune cytopenia; AICDA, activation induced cytidine deaminase; AIHA, autoimmune hemolytic anemia; AIRE, autoimmune regulator; AIT, autoimmune thyroid disease; AN, autoimmune neutropenia; ALPS, autoimmune lymphoproliferative syndrome; APECED, autoimmune polyendocrinopathy–candidiasis–ectodermal dystrophy; APLA, antiphospholipid antibodies; BTK, Bruton tyrosine kinase; CASP10, caspase 10; CD25, cluster of differentiation 25 (interleukin-2 receptor α chain); CGD, chronic granulomatous disease; CNS, central nervous system; CVID, common variable immunodeficiency; CTLA4, cytotoxic T-lymphocyte antigen 4; CYBB, cytochrome B-245 β chain; FAS, FS-7 associated surface antigen; FASLG, FAS ligand; FOXN1, forkhead box N1; FOXP3, forkhead box P3; GATA2, GATA binding protein 2; GN, glomerulonephritis; HIGM, hyperimmunoglobulin M syndrome; HLH, hemophagocytic lymphohistiocytosis; IKBKG, inhibitor of nuclear factor κ B kinase subunit gamma; IKZF1, IKAROS family zinc finger 1; IL2RG, interleukin-2 receptor gamma subunit; ITP, immune thrombocytopenia; LS, leaky severe combined immunodeficiency; Lo-CID, late-onset combined immunodeficiency; LRBA, lipopolysaccharide responsive beige-like anchor protein; NCF1/2, neutrophil cytosolic factor 1 and 2; NFKB1/2, nuclear factor κ B subunits 1 and 2; OS, Omenn syndrome; P-CID, profound combined immunodeficiency; pDGS, partial DiGeorge syndrome; PIK3CD, phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit delta; RAG, recombinase activating gene; SCID, severe combined immunodeficiency; sIgAD, secretory immunoglobulin A deficiency; SLE, systemic lupus erythematosus; STAT5B, signal transducer and activator of transcription 5B; STAT1/3-GOF (S1/3GOF), signal transducer and activator of transcription 1 and 3 gain-of-function mutations; TBX, T-box transcription factor; WAS, Wiskott Aldrich syndrome; XLP1/2, X-linked lymphoproliferative disease 1 and 2; XLA, X-linked agammaglobulinemia.

FIGURE 3

Intrinsic and extrinsic phases of autoimmunity in PID. Autoimmunity in PID arises because of impaired tolerance checkpoints resulting from both intrinsic (genetic susceptibility) and extrinsic (environmental) causes.