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 findingsIn 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, PI3Kd, 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). SummaryClinical presentation of patients with PID and autoimmunity is highly variable and requires in-depth diagnostics and precision medicine approaches.

Immune cytopenias as a continuum in inborn errors of immunity: An in‐depth clinical and immunological exploration

“…The custom panel includes 46 genes involved in the pathogenesis of agammaglobulinemia, CVID, and IEI immune‐dysregulation disorders (Table 1A/1B) based on the last update of the ESID classification 11,12 …”

Case Report: A Novel Pathogenic Missense Mutation in FAS: A Multi-Generational Case Series of Autoimmune Lymphoproliferative Syndrome

“…There is an expanding spectrum of ALPS-like disorders, including caspase 8 deficiency state (CEDS, resulting from a germline mutation in caspase 8 [ CASP8 ]); RAS-associated autoimmune leukoproliferative disease (RALD), resulting from gain of function somatic mutation of the neuroblastoma RAS viral oncogene ( NRAS) or proto-oncogene Kirsten Rat Sarcoma virus ( KRAS) ; X-linked lymphoproliferative syndrome (XLP1) resulting from mutation or deletion of the SH2D1A gene; heterozygous loss of function mutation in nuclear factor kappa light chain enhancer of activated B cells ( NFKB-1 ), heterozygous loss of function mutation of cytotoxic T-lymphocyte associated protein 4 ( CTLA-4 ), and mutations of the FAS -associated protein with death domain (FADD), among others. Approximately one-third of subjects with clinical features of ALPS have unidentified genetic defects ( 1 , 2 , 4 ). Patients with unknown genetic defects but clinical features of ALPS are classified as Dianzani autoimmune lymphoproliferative disease (DALD) ( 2 ).…”

Primary Immune Regulatory Disorders and Targeted Therapies

“…Primary immune regulatory disorders (PIRDs) are a subgroup of IEIs characterized by heterogeneous clinical phenotypes, predominated by autoimmunity, lymphoproliferation, autoinflammation, and malignancy [ 2 , 3 , 4 , 5 ]. These disorders develop from a breakdown in the immune tolerance pathways that can affect different levels of the immune system, modeling various mechanisms for disease development and governing autoimmunity ( Table 1 ).…”

“…Mutations in various genes have been associated with these diseases and the prototype disorder is immune dysregulation, polyendocrinopathy, enteropathy, X-linked (IPEX) [ 6 , 7 , 8 ], caused by mutations in the Forkhead Box P3 (FOXP3) gene, leading to defective CD4+CD25+ regulatory T-cell (Treg) production and described as a Treg defect (Tregopathies; Table 2 ) [ 9 ]. Additional studies later revealed many different genes that pave the way for reclassification of the patients previously described as having combined immune deficiency (CID) or common variable immunodeficiency (CVID) to monogenic PIRD; some of these cases are also accepted as IPEX- and ALPS-like disorders [ 2 , 7 ]. The presenting symptoms might be quite different than increased frequency of infections and the underlying immune dysregulatory disorders can lead to multiple autoimmunities, lymphoproliferation, and malignancies ( Figure 1 ).…”

“…This new concept of therapeutic approaches, known as targeted therapies or precision therapy, is a newly discovered area in medicine in which medical treatment is tailored according to the affected pathways of disease. In many PIRDs, precise therapies have altered the aberrant immune response and resolved the severe autoimmune phenomena in patients, providing better disease control compared to conventional immunosuppressants [ 2 , 12 , 13 , 14 ]. However, long-term effects and risk of infection and malignancy are ambiguous for these therapies and need further clarity.…”