WHIM syndrome: Immunopathogenesis, treatment and cure strategies

Abstract

Summary WHIM syndrome is a rare, autosomal dominant immunodeficiency which is named for the four key manifestations: Warts, Hypogammaglobulinemia, Infections, and Myelokathexis. It results from heterozygous gain‐of‐function mutations in the chemokine receptor CXCR4 which is widely expressed on leukocytes and has profound influences on immune system homeostasis and organogenesis. New treatments for the disease using drugs to reduce CXCR4 function are excellent examples of precision medicine. Since CXCR4 and its ligand CXCL12 play an important role in a variety of infectious, inflammatory, autoimmune, and malignant diseases, the study of WHIM syndrome provides important insights into both the physiologic and disease roles of these molecules.

New Insights on the Emerging Genomic Landscape of CXCR4 in Cancer: A Lesson from WHIM

“…All 17 identified mutations result in both FS and NS mutations in the C-terminal region (C-ter) of the receptor ( Figure 2) and are currently defined as WHIM-like mutations, as they closely resemble the already documented germline, activating mutations of CXCR4 C-ter occurring in heterozygosis in WHIM (warts, hypogammaglobulinemia, infection, and myelokathexis) syndrome (Online Mendelian Inheritance in Man (OMIM) 193670), a congenital autosomal dominant immunodeficiency disorder [88]. WHIM patients and their family members indeed carry several NS mutations (R334*, G336*, S338*, E343*), as well as FS (G323fs, L329fs, S339fs, S341fs) and missense (MS: E343K) mutations [89][90][91], which result in gain-of-function variants of CXCR4 [92] (see Appendix A, Figure 2). Recently, it has been reported that about 3.8% of all mutations occurring in the B-cell-receptor-CXCR4 signaling pathways identified in patients with follicular lymphoma (FL) affect the CXCR4 receptor [93].…”

“…WM is a rare form of nHL or lymphoplasmacytic lymphoma (LPL/WM) [91], with characteristic lymphoplasmacytic infiltration in the BM lymph nodes and spleen, along with the presence of monoclonal immunoglobulin M (IgM) protein in the blood [92]. The current therapeutic armamentarium relies on chemotherapy from nucleoside analogs to alkylating agents and proteasome inhibitors, and subsequently, the integration of rituximab, an anti-CD20 monoclonal antibody that now serves as the cornerstone of anti-LPL/WM regimens [93].…”

“…Moreover, this evidences clearly indicates that NS and FS mutations behave differently. In WHIM syndrome, very few patients carry FS mutations, whereas NS mutations have been identified in almost all patients [92,153]. Unfortunately, currently no preclinical modeling has been done to understand the activating nature of FS mutations.…”

“…This region hosts several serine and threonine residues that are phosphorylated by G protein-coupled Receptor Kinase (GRK) kinases upon CXCL12 activation to facilitate β-arrestin recruitment and clathrin-dependent receptor internalization and degradation, thereby promoting receptor desensitization. All but one of the CXCR4 mutations truncate this region, four by premature termination (NS: R334*, G336*, S338*, E343*) and four by frameshifts (FS: G323fs343*, L329fs341*, S339fs342*, S341fs365*) that introduce 3 to 24 additional new amino acids [88,91,92,146,153]. To date, the only exception to the rule is represented by one different type of mutation that causes a change in the net charge of the C-ter (MS: E343K).…”

Introduction: Continuing insights into the healthy and diseased immune system through human genetic investigation

“…In this issue, we take an eclectic approach, drawing upon the expertise of illustrious and accomplished research groups. Most reviews focus on specific disease entities linked to single gene defects, that are now listed in the Online Mendelian Inheritance in Man (OMIM), such as DOCK8 deficiency (OMIM 611432), Complement hyperactivation, angiopathic thrombosis and protein‐losing enteropathy hyperactivation (CHAPLE, OMIM 226300), CTLA‐4 haploinsufficiency with autoimmunity and inflammation (CHAI, OMIM 616100), autoimmune lymphoproliferative syndrome (ALPS, OMIM six601859) and Ras‐associated lymphoproliferative disease (RALD, OMIM 614470) due to Fas and Ras mutations, respectively, ADA2 deficiency (OMIM 615688), Omenn syndrome (OMIM 603554) and other deficits of the recombinase activating genes RAG1 and RAG2 (OMIM 179615), warts, hypogammaglobulinemia, immunodeficiency, and myelokathexis (WHIM, OMIM 193670) syndrome due to CXCR4 mutations, autoimmune polyendocrinopathy with candidiasis and ectodermal dystrophy (APECED) due to AIRE gene mutations (OMIM 240300), Wisott‐Aldrich syndrome and actin regulatory protein deficiencies due to WAS and WIP mutations, among others . In addition, there are reviews on classes of disorders, such as allergy and atopy, common variable immunodeficiency, early‐onset inflammatory bowel disease, and Chromosome 22.q11.2 and DiGeorge syndrome .…”