Overview of secondary immunodeficiency.

In contrast to inborn errors of immunity (IEI), which are inherited disorders of the immune system that predispose to infections, malignancy, atopy, and immune dysregulation, secondary immunodeficiencies and immune dysregulation states (SID) are acquired impairments in immune cell function and/or regulation, and may be transient, reversible, or permanent. SIDs can derive from a variety of medical comorbidities, including protein-losing conditions, malnutrition, malignancy, certain genetic syndromes, prematurity, and chronic infections. Medications, including immunosuppressive and chemotherapeutic drugs, can have profound effects on immunity and biologic agents used in rheumatology, neurology, and hematology/oncology practice are increasingly common causes of SID. Iatrogenic factors, including surgical procedures (thymectomy, splenectomy) can also contribute to SID. A thorough case history, medication review, and laboratory evaluation are necessary to identify the primary driver and determine proper management of SID. Careful consideration should be given to whether a primary IEI could be contributing to autoimmunity, malignancy, and posttreatment complications (e.g., antibody deficiency). SID management consists of addressing the driving condition and/or removing the offending agent if feasible. If SID is suspected to be permanent, then antibiotic prophylaxis, additional immunization, and immunoglobulin replacement should be considered.

IL-17-Dependent Dysregulated Cutaneous Immune Homeostasis in the Absence of the Wiskott-Aldrich Syndrome Protein.

Wiskott-Aldrich Syndrome (WAS) is characterized by recurrent infections, thrombocytopenia, and eczema. Here, we show that WASp-deficient mice on a BALB/c background have dysregulated cutaneous immune homeostasis with increased leukocyte accumulation in the skin, 1 week after birth. Increased cutaneous inflammation was associated with epithelial abnormalities, namely, altered keratinization, abnormal epidermal tight junctional morphology and increased trans-epidermal water loss; consistent with epidermal barrier dysfunction. Immune and physical barrier disruption was accompanied by progressive skin dysbiosis, highlighting the functional significance of the disrupted cutaneous homeostasis. Interestingly, the dysregulated immunity in the skin preceded the systemic elevation in IgE and lymphocytic infiltration of the colonic lamina propria associated with WASp deficiency. Mechanistically, the enhanced immune cell accumulation in the skin was lymphocyte dependent. Elevated levels of both Type 2 (IL-4, IL-5) and Type 17 (IL-17, IL-22, IL-23) cytokines were present in the skin, as well as the 'itch' factor IL-31. Unexpectedly, the canonical WAS-associated cytokine IL-4 did not play a role in the immune dysfunction. Instead, IL-17 was critical for skin immune infiltration and elevation of both Type 2 and Type 17 cytokines. Our findings reveal a previously unrecognized IL-17-dependent breakdown in immune homeostasis and cutaneous barrier integrity in the absence of WASp, targeting of which may provide new therapeutic possibilities for the treatment of skin pathologies in WAS patients.