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The noncanonical NF-κB pathway is implicated in diverse biological and immunological processes. Monoallelic C-terminus loss-of-function and gain-of-function mutations of NFKB2 have been recently identified as a cause of immunodeficiency manifesting with common variable immunodeficiency (CVID) or combined immunodeficiency (CID) phenotypes. Herein we report a family carrying a heterozygous nonsense mutation in NFKB2 (c.809G A, p.W270*). This variant is associated with increased mRNA decay and no mutant NFKB2 protein expression, leading to NFKB2 haploinsufficiency. Our findings demonstrate that bona fide NFKB2 haploinsufficiency, likely caused by mutant mRNA decay and protein instability leading to the transcription and expression of only the wild-type allele, is associated with clinical immunodeficiency, although with incomplete clinical penetrance. Abnormal B cell development, hypogammaglobulinemia, poor antibody response, and abnormal noncanonical (but normal canonical) NF-κB pathway signaling are the immunologic hallmarks of this disease. This adds a third allelic variant to the pathophysiology of NFKB2-mediated immunodeficiency disorders.

The noncanonical NF-κB pathway is implicated in diverse biological and immunological processes. Monoallelic C-terminus loss-of-function and gain-of-function mutations of NFKB2 have been recently identified as a cause of immunodeficiency manifesting with common variable immunodeficiency (CVID) or combined immunodeficiency (CID) phenotypes. Herein we report a family carrying a heterozygous nonsense mutation in NFKB2 (c.809G > A, p.W270*). This variant is associated with increased mRNA decay and no mutant NFKB2 protein expression, leading to NFKB2 haploinsufficiency. Our findings demonstrate that bona fide NFKB2 haploinsufficiency, likely caused by mutant mRNA decay and protein instability leading to the transcription and expression of only the wild-type allele, is associated with clinical immunodeficiency, although with incomplete clinical penetrance. Abnormal B cell development, hypogammaglobulinemia, poor antibody response, and abnormal noncanonical (but normal canonical) NF-κB pathway signaling are the immunologic hallmarks of this disease. This adds a third allelic variant to the pathophysiology of NFKB2-mediated immunodeficiency disorders.

The observation by Shearer (1974) that cytotoxic lymphocytes could be generated against hapten-modified surfaces of syngeneic cells has served as the platform from which many recent studies on the specificity of recognition by effector T cells have been launched. Shearer’s observations have had a twofold impact: (1) they provided, for the first time, the possibility of raising cytotoxic T lymphocytes (CTL) against a defined hapten; and (2) they revealed that lysis of haptenated cells was restricted by the major histocompatibility complex (MHC), in that in murine systems, the effector and haptenated target cell had to share H-2K and/ or H-2D haplotypes for lysis to occur (Shearer, 1974; Forman et al., 1977a,b). This MHC restriction of hapten-specific T killer cells is widely regarded as analogous to similar restriction that exists for cytotoxic cells directed against viral antigens (Zinkernagel and Doherty, 1974), minor histocompatability antigens (Bevan, 1975), and H-Y antigens (Gordon et al., 1975).

There is now considerable evidence that psychiatric illness may be associated with immune dysfunction (Kronfol et al., 1986). We have previously found a decrease of lymphocyte number and percentage in patients with major depression compared to normal and psychiatric control groups (Kronfol et al., 1984).