Immunodeficiency and Autoimmune Enterocolopathy Linked to NFAT5 Haploinsufficiency

Abstract

The link between autoimmune diseases and primary immunodeficiency syndromes has been increasingly appreciated. Immunologic evaluation of a young man with autoimmune enterocolopathy and unexplained infections revealed evidence of immunodeficiency, including IgG subclass deficiency, impaired antigen-induced lymphocyte proliferation, reduced cytokine production by CD8+ T lymphocytes, and decreased numbers of natural killer (NK) cells. Genetic evaluation identified haploinsufficiency of NFAT5, a transcription factor regulating immune cell function and cellular adaptation to hyperosmotic stress, as a possible cause of this syndrome. Inhibition or deletion of NFAT5 in normal human and murine cells recapitulated several of the immune deficits identified in the patient. These results provide evidence of a primary immunodeficiency disorder associated with organ-specific autoimmunity linked to NFAT5 deficiency.

Context‐dependent regulation of Th17‐associated genes and IFNγ expression by the transcription factor NFAT5

“…Our finding that lack of NFAT5 in T cells could worsen inflammatory processes is in line with the recent characterization of the first human patient identified to date with an NFAT5 haploinsufficiency, 60 who presented with an autoimmune enterocolopathy with symptoms resembling inflammatory bowel disease. T lymphocytes of this patient expressed NFAT5 to about 20% of the level found in healthy individuals and had reduced capability to resist hypertonic stress.…”

Elementary immunology: Na+ as a regulator of immunity

“…This observation suggests that increased tonicity, which is present in secondary lymphatic organs [82], favors T cell proliferation. In line with this notion, mice haplodeficient for the central osmostress transcription factor Nfat5 displayed reduced splenocyte proliferation, impaired IgG responses after vaccination [82] and impaired cytokine production by T cells [83]. This further substantiates that high salt-induced pathways play an important role in T cell immunology.…”

Altered expression of nuclear factor of activated T cells, forkhead box P3, and immune‐suppressive genes in regulatory T cells of generalized vitiligo patients

“…In Tregs, NFATs form analogous co‐operative complexes with FOXP3, which then mediate Treg cell function by repressing the expression of cytokines (IL‐2 and IL‐4) and upregulating the Treg cell markers (CTLA‐4 and CD25) (Wu et al, ), thereby activating the Treg suppressor program. The role of NFAT1, NFAT2, and NFAT5 has been explored in animal models of autoimmune diseases, suggesting that their deficiency could impair the function of Tregs and lead to autoimmune diseases (Boland et al, ; Kwon et al, ; Shin et al, ; Vaeth et al, ). These studies indicate that NFATs could be important target molecules for exploring Treg‐mediated pathogenesis of GV.…”