Pathogenesis of Autoimmune Cytopenias in Inborn Errors of Immunity Revealing Novel Therapeutic Targets

Abstract

Autoimmune diseases are usually associated with environmental triggers and genetic predisposition. However, a few number of autoimmune diseases has a monogenic cause, mostly in children. These diseases may be the expression, isolated or associated with other symptoms, of an underlying inborn error of immunity (IEI). Autoimmune cytopenias (AICs), including immune thrombocytopenic purpura (ITP), autoimmune hemolytic anemia (AIHA), autoimmune neutropenia (AN), and Evans’ syndrome (ES) are common presentations of immunological diseases in the pediatric age, with at least 65% of cases of ES genetically determined. Autoimmune cytopenias in IEI have often a more severe, chronic, and relapsing course. Treatment refractoriness also characterizes autoimmune cytopenia with a monogenic cause, such as IEI. The mechanisms underlying autoimmune cytopenias in IEI include cellular or humoral autoimmunity, immune dysregulation in cases of hemophagocytosis or lymphoproliferation with or without splenic sequestration, bone marrow failure, myelodysplasia, or secondary myelosuppression. Genetic characterization of autoimmune cytopenias is of fundamental importance as an early diagnosis improves the outcome and allows the setting up of a targeted therapy, such as CTLA-4 IgG fusion protein (Abatacept), small molecule inhibitors (JAK-inhibitors), or gene therapy. Currently, gene therapy represents one of the most attractive targeted therapeutic approaches to treat selected inborn errors of immunity. Even in the absence of specific targeted therapies, however, whole exome genetic testing (WES) for children with chronic multilineage cytopenias should be considered as an early diagnostic tool for disease diagnosis and genetic counseling.

Paediatric‐onset Evans syndrome: Breaking away from refractory immune thrombocytopenia

“…28 There are many reviews on the ever evolving targeted pharmaceutical agents for patients with AICs secondary to inherited inborn errors of immunity, as well as those disorders characterized as dysregulated immunity or autoinflammatory. 16,18,29 Early recognition of the patient who exhibits associated IM, or who is resistant to firstline therapy should prompt urgent genetic, lymphocyte phenotyping/function and biomarker studies, as secondline therapy choices should take into account any inborn error and immune dysfunction to optimize therapy and decrease morbidity and mortality due to excessive suppression. A summary of current alternative choices for second line therapy that have been utilized for specific gene variants reported in patients with ES are listed in Table 2.…”

Autoimmune Neutropenias: Update on Clinical and Biological Features in Children and Adults

“…In case of an underlying immune dysregulation/deficiency, particularly in childhood, the definition of the causative variants is critical because it may indicate more targeted treatments (eg, mycophenolate mofetil and rapamycin). 98,99…”

“…Various immune‐regulating drugs (eg, cyclosporine, metothrexate, low‐dose cyclophosphamide) have been used in refractory cases, but overall efficacy has not been determined. In case of an underlying immune dysregulation/deficiency, particularly in childhood, the definition of the causative variants is critical because it may indicate more targeted treatments (eg, mycophenolate mofetil and rapamycin) 98,99 …”

Skin manifestations in children with inborn errors of immunity in a tertiary care hospital in Iran

“…1 These defects may lead to increased susceptibility to infectious, autoinflammatory, autoimmune, allergic, and neoplastic manifestations. [2][3][4] Today, more than 400 distinct disorders with IEI are recognized and, with technical advancements in next-generation sequencing, the number is growing rapidly. 5,6 Inborn Errors of Immunity (IEIs) present with highly variable clinical presentations, among which cutaneous involvement is relatively common and occur in nearly 40% of patients with IEI over a lifetime of the disease course.…”

“…Inborn Errors of Immunity (IEIs) are a group of heterogeneous genetic disorders affecting development and function of the immune system 1 . These defects may lead to increased susceptibility to infectious, autoinflammatory, autoimmune, allergic, and neoplastic manifestations 2–4 . Today, more than 400 distinct disorders with IEI are recognized and, with technical advancements in next‐generation sequencing, the number is growing rapidly 5,6 …”