Autoimmune and other cytopenias in primary immunodeficiencies: pathomechanisms, novel differential diagnoses, and treatment

Abstract

Autoimmunity and immune dysregulation may lead to cytopenia and represent key features of many primary immunodeficiencies (PIDs). Especially when cytopenia is the initial symptom of a PID, the order and depth of diagnostic steps have to be performed in accordance with both an immunologic and a hematologic approach and will help exclude disorders such as systemic lupus erythematosus, common variable immunodeficiency, and autoimmune lymphoproliferative syndromes, hemophagocytic disorders, lymphoproliferative diseases, and novel differential diagnoses such as MonoMac syndrome (GATA2 deficiency), CD27 deficiency, lipopolysaccharide-responsive beige-like anchor (LRBA) deficiency, activated PI3KD syndrome (APDS), X-linked immunodeficiency with magnesium defect (MAGT1 deficiency), and others. Immunosuppressive treatment often needs to be initiated urgently, which impedes further relevant immunologic laboratory analyses aimed at defining the underlying PID. Awareness of potentially involved disease spectra ranging from hematologic to rheumatologic and immunologic disorders is crucial for identifying a certain proportion of PID phenotypes and genotypes among descriptive diagnoses such as autoimmune hemolytic anemia, chronic immune thrombocytopenia, Evans syndrome, severe aplastic anemia/refractory cytopenia, and others. A synopsis of pathomechanisms, novel differential diagnoses, and advances in treatment options for cytopenias in PID is provided to facilitate multidisciplinary management and to bridge different approaches.

Figure 1

Synopsis of cytopenias in PID. Conceptual overview, excluding primary defects of phagocyte number or function, inherited non-PID bone marrow failure syndromes, and disorders of isolated lymphopenia (without other cytopenia). *Includes hypomorphic mutations in SCID genes, CD40, CD40L, and other combined immunodeficiencies such as radiosensitive disorders, defects in the Ca⁺⁺ channel, and activating PI3K syndrome. AIHA, autoimmune hemolytic anemia; AIN, autoimmune neutropenia; CHH, cartilage hair hypoplasia; CHS, Chediak-Higashi syndrome; DKC, dyskeratosis congenita; FHL1-5, familial hemophagocytic lymphohistiocytosis 1-5; HPS-2, Hermansky-Pudlak syndrome 2; ITK, IL-2–inducible T-cell kinase deficiency; LRBA, lipopolysaccharide-responsive beige-like anchor deficiency; PNH, paroxysmal nocturnal hemoglobinuria; RCC, refractory cytopenia of childhood; RD, reticular dysgenesis; SCN1, severe congenital neutropenia 1; SDS, Shwachman-Diamond syndrome; WHIM, warts, hypogammaglobulinemia, immunodeficiency, myelokathexis; WIP, WAS protein-interacting protein; XLP-1,2, X-linked lymphoproliferative disease 1,2.