Brief Summary: Treatment of the autoimmune and immune-dysregulatory features of patients with STAT1 GOF or STAT3 GOF disease remains challenging. Jakinibs have been used to treat the severe immune-dysregulation in patients with either STAT1 GOF or STAT3 GOF mutations.

Primary antibody deficiencies (PADs) are the most common form of primary immunodeficiency and predispose to severe and recurrent pulmonary infections which can result in chronic lung disease including bronchiectasis. Chronic lung disease is among the most common complications of PAD and a significant source of morbidity and mortality for these patients. However, the development of lung disease in PAD may not be solely the result of recurrent bacterial infection or a consequence of bronchiectasis. Recent characterization of monogenic immune dysregulation disorders and more extensive study of common variable immunodeficiency has demonstrated that interstitial lung disease (ILD) in PAD can result from generalized immune dysregulation and frequently occurs in the absence of pneumonia history or bronchiectasis. This distinction between bronchiectasis and ILD has important consequences in the evaluation and management of lung disease in PAD. For example, treatment of ILD in PAD typically utilizes immunomodulatory approaches in addition to immunoglobulin replacement and antibiotic prophylaxis which are the stalwarts of bronchiectasis management in these patients. Additionally, while all antibody deficient patients are at risk of developing bronchiectasis, ILD occurs in some forms of PAD much more commonly than others, suggesting that distinct but poorly understood immunological factors underlie development of this complication. Importantly, ILD can have earlier onset and may worsen survival more than bronchiectasis. Further efforts to understand the pathogenesis of lung disease in PAD will provide vital information for the most effective methods of diagnosis, surveillance, and treatment of these patients.

Properly regulated STAT1 signaling is critical for NK cell maturation and function. Modulation of increased STAT1 phosphorylation with ruxolitinib is an important option for therapeutic intervention in patients with STAT1 GOF mutations.

Background. Naturally occurring botulism is rare, but a large number of cases could result from unintentional or intentional contamination of a commercial food. Despeciated, equine-derived, heptavalent botulinum antitoxin (HBAT) is licensed in the United States. Timely treatment reduces morbidity and mortality, but concerns that botulinum antitoxin can induce anaphylaxis exist. We sought to quantify the allergy risk of botulinum antitoxin treatment and the usefulness of skin testing to assess this risk.Methods. We conducted a systematic review of (1) allergic reactions to botulinum antitoxin and (2) the predictive value of skin testing (ST) before botulinum antitoxin administration. We searched 5 scientific literature databases, reviewed articles' references, and obtained data from the HBAT manufacturer and from the Centers for Disease Control and Prevention. Anaphylaxis incidence was determined for HBAT and previously employed botulinum antitoxins. We calculated the positive predictive value (PPV) and negative predictive value (NPV) of ST for anaphylaxis related to HBAT and other botulinum antitoxins.Results. Seven articles were included. Anaphylaxis incidence was 1.64% (5/305 patients) for HBAT and 1.16% (8/687 patients) for all other botulinum antitoxins (relative risk, 1.41 [95% confidence interval, .47-4.27]; P = .5). Observed values for both PPV and NPV for HBAT-ST (33 patients) were 100%. Observed PPVs and NPVs of ST for other botulinum antitoxins (302 patients) were 0-56% and 50%-100%, respectively. There were no reports of fatal anaphylaxis.Conclusions. Considering the <2 % rate of anaphylaxis, fatal outcomes, modest predictive value of ST, resource requirements for ST, and the benefits of early treatment, data do not support delaying HBAT administration to perform ST in a mass botulinum toxin exposure. Anaphylactic reactions may occur among 1%-2% of botulinum antitoxin recipients and will require epinephrine and antihistamine treatment and, possibly, intensive care.

36 37 Funding sources: Chao Physician Scientist Junior Faculty Award (LRF), NIAID 38 R01 AI120989 (JSO), Jeffrey Modell Foundation Diagnostic and Research 39 Center for Primary Immunodeficiencies. 40 41 Disclosure of conflicts of interest: 42 The authors declare no conflict of interest 43 44 45 46 Word count: 4231 47 Abstract word count: 209 Key Message: In vivo and in vitro treatment with the JAK inhibitor ruxolitinib 52 partially restores perforin expression and cytotoxic function in immature CD56 dim 53 NK cells from patients with STAT1-gain of function (GOF) mutations. 54 55 Capsule Summary: Patients with heterozygous gain-of-function STAT1 56 mutations develop an NK cell deficiency characterized by impaired perforin 57 expression and poorly functional NK cells that fail to mature. JAK inhibition with 58 ruxolitinib restores perforin expression, thus augmenting NK cell function and 59 providing a possible therapeutic intervention. 60 61

Infantile systemic hyalinosis (ISH) is a rare autosomal recessive disorder and an allelic form of hyaline fibromatosis syndrome that is caused by mutations in the ANTRX2 gene encoding the transmembrane anthrax toxin receptor 2. Its main features include characteristic skin lesions, joint contractures, persistent diarrhea, and failure to thrive due to accumulation of hyaline material in multiple organs. The resulting severe malnutrition can cause death in early infancy. Because of its rarity and high fatality rate, timely diagnosis is difficult and ISH may be underdiagnosed. In this report, we describe a 10-month-old male with severe protein-losing enteropathy, skin lesions, and painful joint contractures, diagnosed with ISH based on skin his-topathology and identification of a novel homozygous ANTRX2 mutation, c.1127_1128delTG (p.V376Gfs*14). While its clinical outcome is poor without curative treatment, establishing a diagnosis of ISH starting from clinical suspicion to molecular analysis is important for appropriate medical management and for risk and carrier assessment of family members.

IgE-mediated food allergies are an important public health problem, affecting 5 % of adults and 8 % of children, with numerous studies indicating that the prevalence is increasing. Food allergic reactions can range in severity from mild to severe and life threatening. Accurate diagnosis of food allergy is necessary not only to provide appropriate and potentially life-saving preventive measures but also to prevent unwarranted dietary restrictions. The diagnosis of food allergy has traditionally been based on clinical history and food specific IgE (sIgE) testing, including skin prick testing (SPT), serum tests, or both. These tests tend to be extremely sensitive, but positive test results to foods that are tolerated are common. Studies of allergen component-resolved diagnostics (CRD) show that adjuvant use of this modality may provide a more accurate assessment in the diagnosis of food allergy, though the reported benefits are questionable for a number of major allergens. Furthermore, diagnostic cutoff values have been difficult to determine for allergens where component testing has been demonstrated to be beneficial.

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