Finding 1: Because of our interest in patients with symptoms of atopy in the context of unidentified syndromes, we have been studying a series of families with cold urticaria, antibody deficiency, autoimmunity and granulomatous disease segregating in an autosomal dominant pattern. We have named this syndrome PLAID, as described in our report in the New England Journal of Medicine. Patients have low IgM and IgA, low NK cells, normal T cells and low to absent class-switched B cells. In collaboration with Dr. Daniel Kastner's lab, we found that the disease is caused by genomic deletions in PLCG2. The deletions are in an autoregulatory domain, leading to gain of PLCG2 enzymatic function but loss of distal signaling function, resulting in defective calcium flux and ERK phosphorylation in response to surface receptor cross-linking in B and NK cells, poor in vitro expansion and switched immunoglobulin secretion in response to SAC and CpG, and abnormal B-cell receptor editing in B-cells. We have found that the cold spontaneously activates certain cells in these patients, such as B cells and mast cells. We have since found that cold also activates neutrophils and monocytes from these patients, and have further described the neonatal onset rash, and subsequent adult-onset granulomatous disease in 7 patients with PLAID, which may be due to the cooler temperatures in the skin activating neutrophils and monocytes. In addition, we have found 4 new families with symptoms identical to PLAID, but who lack any mutations or deletions in PLCG2, suggesting a set of genes may be capable of causing PLAID. A report describing these findings is in review now. Finding 2: In our study of patients with immune deficiencies and atopic phenotypes, we have developed a flow-based assay for assessing multiple STAT responses to individual cytokines. Using this tool, in collaboration with Dr. Steve Holland's lab, we have found a family with invasive cryptosporidial infections, bronchiectasis and antibody deficiency with marked elevations in serum IgE. We found absent IL-21 signaling in these patients. In collaboration with Christoph Klein in Munich, we found a 6 bp in-frame deletion in the IL-21 receptor in these patients. Dr. Klein had followed two patients with similar phenotypes and found an independent mutation in the IL-21 receptor. The report of ours and Dr. Klein's patients was published in the Journal of Experimental Medicine. In addition, we have used this tool to identify patients with gain of function mutations in STAT1 from the Holland lab and in collaboration with Neil Romberg at Yale, which lead to a variety of clinical phenotypes, and we have made inroads into the pathogenesis of these mutations leading to the discrete phenotypes. Three different manuscripts describing these findings were published in the Journal of Allergy and Clinical Immunology. The clinical and laboratory overlap between STAT3 loss-of-function patients, STAT1 gain-of-function patients, and IL-21r loss of function patients can be gleaned from these various reports, and provides the basis for ongoing investigation into these common pathways. Finding 3: Using whole exome sequencing, we found recessive mutations in phosphoglucomutase 3 (PGM3) which lead to a syndrome of severe allergy, immune deficiency and neurocognitive abnormalities. The patients have severe atopic dermatitis and high IgE, as well as high IgA and IgG, low CD8 and memory B-cell numbers, dysmyelination, and abnormally increased Th2 and Th17 cytokine production. The mutations in PGM3 lead to a reduction in normal protein glycosylation and segregate perfectly with disease in two different multiplex families affected. Of significant importance, exogenous N-acetyl glucosamine, a substrate upstream of PGM3, was able to correct an observed deficit in cytoplasmic UDP-N-acetyl glucosamine, suggesting that exogenous sugars and/or sugar amines might be able to correct the defect found in these patients. The results were published in the Journal of Allergy and Clinical Immunology. Finding 4: In our efforts to describe familial inheritance of allergic disease, we have identified 25 families with an autosomal dominant inheritance of elevated basal tryptase levels in the absence of any signs of mastocytosis. Affected family members have cutaneous flushing, episodic gastrointestinal pain, food allergy and anaphylaxis, and, in a subset of patients, connective tissue abnormalties reminiscent of Ehlers-Danlos syndrome, hypermobility type. Patient basophils have a degranulation defect, perhaps due to anergy ex-vivo, and in the multiple families in whom bone marrow biopsies were done, there was a significant elevation in mast cell number, despite the complete lack of morphologic evidence or scale of mastocytosis. A report describing our experience with the first 9 families was published in the Journal of Allergy and Clinical Immunology.

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Ma, Chi A; Xi, Liqiang; Cauff, Brian et al. (2017) Somatic STAT5b gain-of-function mutations in early onset nonclonal eosinophilia, urticaria, dermatitis, and diarrhea. Blood 129:650-653
Schwerd, Tobias; Twigg, Stephen R F; Aschenbrenner, Dominik et al. (2017) A biallelic mutation in IL6ST encoding the GP130 co-receptor causes immunodeficiency and craniosynostosis. J Exp Med 214:2547-2562
Lyons, J J; Liu, Y; Ma, C A et al. (2017) ERBIN deficiency links STAT3 and TGF-? pathway defects with atopy in humans. J Exp Med 214:669-680
Tangye, Stuart G; Forbes, Lisa R; Leiding, Jennifer et al. (2017) Low IgE Is Insufficiently Sensitive to Guide Genetic Testing of STAT3 Gain-of-Function Mutations. Clin Chem 63:1539-1540
Ma, Chi A; Stinson, Jeffrey R; Zhang, Yuan et al. (2017) Germline hypomorphic CARD11 mutations in severe atopic disease. Nat Genet 49:1192-1201
Zhang, Yuan; Ma, Chi A; Lawrence, Monica G et al. (2017) PD-L1 up-regulation restrains Th17 cell differentiation in STAT3 loss- and STAT1 gain-of-function patients. J Exp Med 214:2523-2533
Carlson, Ryan J; Bond, Michelle R; Hutchins, Shermaine et al. (2017) Detection of phosphoglucomutase-3 deficiency by lectin-based flow cytometry. J Allergy Clin Immunol 140:291-294.e4
Weinreich, Michael Alexander; Vogel, Tiphanie P; Rao, V Koneti et al. (2017) Up, Down, and All Around: Diagnosis and Treatment of Novel STAT3 Variant. Front Pediatr 5:49
Zhou, Qing; Wang, Hongying; Schwartz, Daniella M et al. (2016) Loss-of-function mutations in TNFAIP3 leading to A20 haploinsufficiency cause an early-onset autoinflammatory disease. Nat Genet 48:67-73
Toubiana, Julie; Okada, Satoshi; Hiller, Julia et al. (2016) Heterozygous STAT1 gain-of-function mutations underlie an unexpectedly broad clinical phenotype. Blood 127:3154-64

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