A kindred with mutant IKAROS and autoimmunity

Abstract

IKAROS (encoded by IKZF1) is an important hematopoietic transcription factor critical for early B cell differentiation, with major defects known to lead to low B cell numbers and hypogammaglobulinemia. More perplexing is the link between IKZF1 variants and autoimmunity, including polymorphisms associated with susceptibility to SLE, and recently, rare variants driving monogenic autoimmunity. We identified a novel p.L188V mutation in IKZF1 in the index patient and her father and found this mutation to lead to loss of DNA binding. Peripheral B cells lacking a full complement of IKAROS function show upregulation of molecules accentuating B cell activation, while CD22, a key negative feedback circuit, is suppressed. The resulting hyperresponsiveness of peripheral B cells, in combination with elevated follicular helper T cell (Tfh) numbers, provides a putative mechanistic explanation for the association of IKZF1 variants with the emergence of autoimmune manifestations in this kindred.

Assessing the Functional Relevance of Variants in the IKAROS Family Zinc Finger Protein 1 (IKZF1) in a Cohort of Patients With Primary Immunodeficiency

“…Thus, it could be possible that the elevated percentage of the transitional B cells could be rather the consequence of a decrease percentage of another lymphocyte population such as CD27 memory B cells. Previous T cell studies in CVID patients with IKZF1 mutations showed a consistent increase in the number CD8 + T cells with reversed CD4:CD8 ratios as the result of increased CD8 + T-cell counts (16, 35, 36). In addition, increased number of CD8 + T cells was also observed in three CID patients reported by Boutboul and colleagues.…”

Familial Immune Thrombocytopenia Associated With a Novel Variant in IKZF1

“…Together with our patients, to date approximately 60 cases from 19 unrelated families have been reported to have 14 unique germline heterozygous IKZF1 mutations, including missense, splice site, frameshift, partial- and whole-gene deletions (3, 5–9, 13) (Figure 1B). The most common primary clinical presentation is recurrent infections (25/60) and is followed by hematologic and autoimmune manifestations.…”

“…Patients with heterozygous germline loss-of-function (LOF) IKZF1 variants mainly present with autosomal dominant antibody deficiencies (B-cell defects and dysgammaglobulinemia) and abnormal hematopoiesis (3, 5). In previous reports, their presentations varied from being asymptomatic to recurrent infections, autoimmunity, cytopenias, and T- or B-ALL (3–9). The increased risk of autoimmunity in IKAROS haploinsufficiency might be explained by the lower threshold for activation caused by decreased CD22 expression on mutant B lymphocytes (9).…”

“…In previous reports, their presentations varied from being asymptomatic to recurrent infections, autoimmunity, cytopenias, and T- or B-ALL (3–9). The increased risk of autoimmunity in IKAROS haploinsufficiency might be explained by the lower threshold for activation caused by decreased CD22 expression on mutant B lymphocytes (9). Germline dominant negative mutations (DN) have been linked to early-onset combined immunodeficiency and B-ALL (7, 10).…”

Defective Sec61α1 underlies a novel cause of autosomal dominant severe congenital neutropenia

“…Whole exome sequencing and filtering were performed as previously described. 23 For details, please refer to the Supplemental Data provided in this article’s Online Repository at www.jacionline.org .…”