DeCure for Immunodeficiency 89 and autoimmunity

DOCK8 immunodeficiency syndrome (DIDS) is a combined immunodeficiency marked by recurrent viral infections, severe atopy, and early onset malignancy. Genetic studies found large, unique deletions in patients from different families and ethnic backgrounds. Clinical markers include atopic dermatitis, allergies, cutaneous viral infections, recurrent respiratory tract infections, and malignancy. Immune assessments showed T cell lymphopenia, hyper-IgE, hypo-IgM, and eosinophilia. Impaired lymphocyte functions appear central to disease pathogenesis.

Common variable immunodeficiency (CVID) is a heterogeneous group of primary antibody deficiency. Patients have increased susceptibility to infections and low serum immunoglobulin, but enteropathy, granulomatous organ infiltrates, malignancy, inflammatory and autoimmune conditions are also prevalent. The coexistence of immunodeficiency and autoimmunity creates difficulties in management because immune dysregulation and persistent inflammation impair diagnosis and treatment. Among combined immunodeficiency disorders, the highest incidence of autoimmunity is described in autoimmune polyendocrine syndrome 1, LRBA deficiency, CTLA-4 deficiency, and STAT-related disorders. The pathogenesis of autoimmunity in immunodeficiency is not fully elucidated, but altered germinal centre reactions, impaired lymphocyte negative selection, uncontrolled lymphocyte proliferation, ineffective cytoskeletal function, innate immune defects, and defective clearance of infectious agents play a role.

For patients with significant antibody deficiencies, immunoglobulin therapy is the mainstay of treatment and significantly reduces both the frequency and severity of infections. Formulations and delivery methods have evolved to increase access. In HIV infection, chronic immune activation with progressive immune exhaustion are central features; the role of self-reactive T cells in generating and maintaining this process has been described, but the impact of immune dysregulation on autoimmune phenomena in HIV remains incompletely understood. The cause, frequency and prognosis of autoimmune conditions associated with HIV are somewhat uncertain, and management is often empirical with novel immunosuppressive medication.

What is still missing are targeted treatments for the specific genetic defects in DOCK8 deficiency and other combined immunodeficiencies with autoimmunity, as well as prospective trials that stratify patients by underlying genetic cause rather than by clinical phenotype alone. The diagnostic algorithm proposed for primary immunodeficiencies in patients with autoimmunity has not been validated in large, diverse populations. Funding for mechanistic studies linking specific immune defects to autoimmune manifestations, and for trials of therapies that do not further impair host defence, remains inadequate.