Immunodeficiency due to defects in store-operated calcium entry

Abstract

Mutations in genes encoding the calcium-release activated calcium (CRAC) channel abolish calcium influx in cells of the immune system and cause severe congenital immunodeficiency. Patients with autosomal recessive mutations in the CRAC channel gene ORAI1, its activator stromal interaction molecule 1 (STIM1), and mice with targeted deletion of Orai1, Stim1, and Stim2 genes reveal important roles for CRAC channels in adaptive and innate immune responses to infection and in autoimmunity. Because CRAC channels have important functions outside the immune system, deficiency of either ORAI1 or STIM1 is associated with a unique clinical phenotype. This review will give an overview of CRAC channel function in the immune system, examine the consequences of CRAC channel deficiency for immunity in human patients and mice, and discuss genetic defects in immunoreceptor-associated signaling molecules that compromise calcium influx and cause immunodeficiency.

Figure 1. Store-operated Ca²⁺ entry (SOCE) through CRAC channels and its functions in immune cells

SOCE in T, B, NK and mast cells, neutrophils and macrophages is induced by engagement of immunoreceptors such as the TCR, BCR, Fcγ and Fcε receptors and activating NK cell receptors. The activation of PLCγ1 and PLCγ2 results in the production of InsP₃ and the release of Ca²⁺ from ER Ca²⁺ stores via the opening of InsP3 receptor channels. The resulting decrease of the [Ca²⁺]_ER is sensed by STIM1 and STIM2, which translocate to ER-plasma membrane junction where they bind to and activate ORAI1 CRAC channels. The resulting sustained Ca²⁺ influx activates Ca²⁺ regulated enzymes such as calcineurin and is required for the transcription of many genes (especially cytokine genes regulated by the Ca²⁺/calcineurin dependent transcription factor NFAT). SOCE is necessary for the degranulation and cytotoxic function of CD8⁺ T cells and NK cells, phagocytosis by macrophages, and production of reactive oxygen species in neutrophils. Abbreviations: CRAC, Ca²⁺ release activated Ca²⁺ channels; ER, endoplasmic reticulum; InsP3, inositol-1,4,5-trisphosphate; NFAT, nuclear factor of activated T cells; PLC, phospholipases C; STIM, stromal interaction molecule.

Figure 2. Mutations in ORAI1 and STIM1 genes abolish SOCE and cause immunodeficiency

Autosomal recessive mutations in the human ORAI1 and STIM1 genes abolish CRAC channel function by interfering with ORAI1 or STIM1 mRNA expression (red), protein expression (orange) or their function (green). Protein domains in STIM1 are shown as shaded boxes (abbreviations: CC, coiled-coil domain; EFh, EF hand domain; SAM, sterile alpha motif; S/P, serine/proline rich). For details see text.

Figure 3. Synopsis of the clinical phenotype in CRAC channelopathy

Autosomal recessive mutations in ORAI1 and STIM1 are associated with a unique clinical phenotype that is characterized by (1) severe immunodeficiency (despite normal leukocyte numbers), (2) autoimmune cytopenias and hepatosplenomegaly / lymphadenopathy, (3) congenital, global muscular hypotonia and partial iris hypoplasia, (4) ectodermal dysplasia (anhidrosis and hypocalcified amelogenesis imperfecta, type III). Muscular hypotonia correlates histologically with a predominance of slow twitch (type I) and atrophy of fast twitch (type II) muscle fibers. Upper panel: H&E stain of a muscle biopsy from a patient with ORAI1-R91W mutation; lower panel: immunofluorescence using anti-ORAI1 and anti-MHC fast antibodies. Common infections and pathogens in ORAI1 and STIM1 deficient patients are listed on the left (for details see Table 1). For a list of abbreviations see Table 1.