TACI deficiency — a complex system out of balance
Introduction
The superfamily of TNF receptors and ligands (TNF(R)SF) are characterized by common biochemical and structural features, yet they contribute to a huge variety of biological processes such as cell growth, cell differentiation and metabolism. In the immune system, TNF(R)SF members act mainly during inflammation and immune defence. Therefore, defects in TNF(R)SF members result in autoinflammatory or autoimmune diseases and immunodeficiency. Finally, novel therapeutic agents, like Atacicept or Belimumab, either neutralize TNF(R)SF members directly or interfere with their downstream signaling pathways. In this respect, the transmembrane activator and calcium-modulator and cyclophilin ligand interactor (TACI) serves as a prototypic example of this group of TNF receptors and is — together with B cell activating factor (BAFF-R) and B-cell maturation antigen (BCMA) part of a small TNF receptor subfamily, mainly expressed on the surface of B-cells and plasma cells.
Section snippets
TACI structure and expression
TACI regulates immune cell homeostasis, differentiation and function and is embedded in a complex network of cytokines, TNFSF ligands, microbial danger signals and its cognate receptors. TACI primarily serves as a receptor for BAFF (B cell activating factor) and APRIL (A proliferation inducing ligand) (Figure 1a). TACI shares binding of BAFF and APRIL with its cognate receptor BCMA whereas BAFF-R can only bind BAFF (see review by Sevdali et al.). TACI and APRIL are both able to also bind
TACI signaling
TACI was originally described as a receptor initiating NF-AT signaling via CAML in T-cells but it mainly signals via the canonical NFkB pathway by recruiting at least two TNF receptor associated factor (TRAF) homotrimers (Figure 1e) [1]. TACI is linked to the Toll-like receptor pathway by a binding site in the ‘TACI highly conserved domain’ (THC) for the TLR-adapter MyD88 (Figure 2). Via MyD88 and its downstream mediators, TACI activates the canonical NFκB pathway inducing TI class switch
TACI mutations in CVID
Mutations in the human TNFRSF13B gene were first described in common variable immunodeficiency (CVID) and selective IgA deficiency [22,23]. The majority of patients with TACI deficiency are sporadic, with no obvious family history of primary immunodeficiency. In familial cases both autosomal dominant and autosomal recessive types of inheritance are present [24,25]; moreover, lack of segregation and incomplete penetrance has been observed [24,26,27]. Even siblings carrying identical deleterious
Clinical associations of TACI deficiency in CVID
Although TACI mutations are not per se disease causing, they are associated with impaired TI antibody responses, benign lymphoproliferation, and an increased rate of autoimmunity [22, 23, 24,28,36•,47]. Lymphoproliferation is observed frequently in CVID patients, yet in CVID patients carrying TACI mutations it seems to be even more abundant [24]. Splenomegaly, lymphadenopathy, and tonsillar hypertrophy are common, often leading to surgical intervention [48]. The mechanisms behind the
Conclusions and outlook
Being one of the first more common genetic abnormality described in patients with CVID, studies of TACI-deficient mouse models and human TACI-deficient cellular models in recent years have been very instructive and unraveled crucial mechanisms in the immune defence going beyond the role of TACI for T-cell independent and IgA class switch recombination. In addition to genetic defects in TACI and its close relatives, other non-genetic disturbances of the BAFF/APRIL ligand and receptor network
Conflict of interest statement
Nothing declared.
References and recommended reading
Papers of particular interest, published within the period of review, have been highlighted as:
• of special interest
•• of outstanding interest
CRediT authorship contribution statement
Ulrich Salzer: Conceptualization, Writing - original draft, Writing - review & editing. Bodo Grimbacher: Writing - review & editing.
Acknowledgements
B.G. is funded by the Deutsche Forschungsgemeinschaft (GR1617/14-1/iPAD; SFB1160/2_B5; RESIST–EXC 2155–Project ID 390874280; and CIBSS–EXC-2189–Project ID 390939984) and the BMBF (GAIN 01GM1910A).
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2023, Human ImmunologyCitation Excerpt :TACI is the receptor for two cytokines: (a) B cell activating factor (BAFF) (also called BLyS) which besides TACI also binds BAFF-R and BCMA (B cell maturation antigen); and (b) “a proliferation inducing ligand” (APRIL), which besides TACI also binds BCMA [12–14]. Binding of BAFF and APRIL to TACI causes intracellular domains of two or more TACI polypeptides to aggregate and to engage TNFR-associated factors (TRAF)-2, -5 and -6, which in turn activate NFκB, c-Jun NH2-terminal kinase (4) and activator protein-1 (AP-1) [10,15–17]. Activated TACI also can interact with calcium-modulating cyclophilin ligand (CAML) of the endoplasmic reticulum to activate NF-AT (most thoroughly studied in T cells).
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