Expanding the Clinical and Immunological Phenotypes and Natural History of MALT1 Deficiency

The role of the CBM complex in allergic inflammation and disease

“…There is significant evidence that aberrant MALT1 activity contributes to the development of AD. As noted earlier, most MALT1-deficient patients (14 of 18) present with AD, 207,208 and aging Malt1 2/2 mice develop AD-like skin inflammation, characterized by acanthosis, hyperkeratosis, parakeratotic scaling, T-cell infiltration, and increased levels of the proinflammatory cytokines TSLP and IL-22. 74,211,224 Interestingly, neither T-cellspecific nor keratinocyte-specific Malt1-deficient mice develop AD, indicating that MALT1 deficiency in both cell types is necessary for the AD phenotype, 211 although the underlying mechanisms are unclear.…”

“…Over the past decade, 20 patients have been identified with MALT1 deficiencies as a result of 18 distinct mutations throughout the MALT1 gene (19 of these patients are summarized by Sefer et al). [199][200][201][202][203][204][205][206][207][208] MALT1deficient patients present with a clinical picture resembling CID, including failure to thrive and increased susceptibility to various bacterial, fungal, and viral infections, but also present with autoimmune diseases (eg, alopecia and vitiligo). Notably, MALT1-deficient patients often exhibit allergic features, with 11 of 15 (77%) patients assessed having eosinophilia, 6 of 17 (35%) having elevated serum IgE, and 14 of 18 (78%) presenting with AD.…”

“…Interestingly, asthma, AR, or food allergy is rarely observed. 207,208 Studies by several groups using 2 main mouse models (Malt1 2/2 and protease-dead [PD] Malt1 PD/PD mice) have given us significant insight into possible mechanisms governing the allergic inflammation in MALT1-deficient patients. Malt1 2/2 mice do not express detectable levels of Malt1 and thus lack both its scaffolding and protease functions.…”

“…S/T, Serine/ threonine. Numbers signify amino acid residues; approximate domain locations are based on Sefer et al 208 Mouse symbol designates the murine Malt1 mutation C472A, which results in Malt1 PD/PD mouse models. 209,210,214 patients, including failure to thrive, cachexia, lymphadenopathy, autoimmune diseases, and widespread inflammation with allergic features (eg, elevated T H 2 cytokines and IgE).…”

“…209,210,214,220 The more severely reduced T-follicular helper (T FH ) population that is observed in Malt1 2/2 mice (which results in attenuated B-cell antibody production) may account for this difference. 208,209 However, it is unclear how the T FH -cell population is affected in MALT1-deficient humans.…”