Brian P. Peppers

Plasma cell deficiency in human subjects with heterozygous mutations in Sec61 translocon alpha 1 subunit (SEC61A1)

Desirée Schubert, Marie-Christine Klein, Sarah Hassdenteufel, Andrés CaballeroOteyza, Linlin Yang, Michele Proietti, Alla Bulashevska, Janine Kemming, Johannes Kühn, Sandra Winzer, Stephan Rusch, Manfred Fliegauf, Alejandro A. Schäffer, Stefan Pfeffer, Roger Geiger, Adolfo Cavalié, Hongzhi Cao, Fang Yang, Yong Li, Marta Rizzi, Hermann Eibel, Robin Kobbe, Amy L. Marks, Brian P. Peppers, Robert W. Hostoffer, Jennifer M. Puck, Richard Zimmermann, Bodo GrimbacherBackground: Primary antibody deficiencies (PADs) are the most frequent primary immunodeficiencies in human subjects. The genetic causes of PADs are largely unknown. Sec61 translocon alpha 1 subunit (SEC61A1) is the major subunit of the Sec61 complex, which is the main polypeptide‐conducting channel in the endoplasmic reticulum membrane. SEC61A1 is a target gene of spliced X‐box binding protein 1 and strongly induced during plasma cell (PC) differentiation. Objective: We identified a novel genetic defect and studied its pathologic mechanism in 11 patients from 2 unrelated families with PADs. Methods: Whole‐exome and targeted sequencing were conducted to identify novel genetic mutations. Functional studies were carried out ex vivo in primary cells of patients and in vitro in different cell lines to assess the effect of SEC61A1 mutations on B‐cell differentiation and survival. Results: We investigated 2 families with patients with hypogammaglobulinemia, severe recurrent respiratory tract infections, and normal peripheral B‐ and T‐cell subpopulations. On in vitro stimulation, B cells showed an intrinsic deficiency to develop into PCs. Genetic analysis and targeted sequencing identified novel heterozygous missense (c.254T>A, p.V85D) and nonsense (c.1325G>T, p.E381*) mutations in SEC61A1, segregating with the disease phenotype. SEC61A1‐V85D was deficient in cotranslational protein translocation, and it disturbed the cellular calcium homeostasis in HeLa cells. Moreover, SEC61A1‐V85D triggered the terminal unfolded protein response in multiple myeloma cell lines. Conclusion: We describe a monogenic defect leading to a specific PC deficiency in human subjects, expanding our knowledge about the pathogenesis of antibody deficiencies.

Scholar 7: The Development of Regional Community Hospitals’ Scholastic Environment

The importance of increasing scholarly activity has been highlighted among residency programs currently accredited by the American Osteopathic Association (AOA) to ensure a smooth transition to the single accreditation system. The Scholar 7 program, a series of seven 2-hour sessions, was created to aid faculty and residents in the pursuit of scholarly work and to facilitate change in an entire community hospital systems environment by creating a self-replicating scholarly culture in a timely and cost-efficient manner. Skills were taught by means of preparation and submission of a research protocol to the institutional review board (IRB) along with grant proposals. The authors tracked scholarly work, IRB submissions, and grants awarded to participants during the 2015-2016 academic year. The results were compared in a post-hoc fashion with previous classes since 2007-2008 within the same hospitals system. The Scholar 7 program successfully aided faculty in achieving their required pursuit of scholarly work in 8 months. This program has the potential to help AOA-focused residency programs meet the scholarly requirements of the Accreditation Council for Graduate Medical Education.

Fetal response to intramuscular epinephrine for anaphylaxis during maternal penicillin desensitization for secondary syphilis

Abstract Penicillin desensitization is indicated in pregnant patients with severe allergies to penicillin with syphilis. The immediate effects of intramuscular epinephrine on the fetus during desensitization remain unreported. We describe a pregnant patient with secondary syphilis and penicillin allergy who developed anaphylaxis during penicillin desensitization. Anaphylaxis resolved after administration of intramuscular epinephrine. Throughout the procedure, continuous electronic fetal monitoring showed a stable fetus without a decrease in variability, tachycardia, decelerations, or signs of fetal distress. This case showed that intramuscular epinephrine is effective in treatment of anaphylaxis in a pregnant patient with little to no immediate effects on the fetus.

Stratification of peanut allergic murine model into anaphylaxis severity risk groups using thermography

Murine models are readily used to investigate mechanisms potentially involved in anaphylaxis. Determining successful sensitization with current methods remain potentially lethal, invasive, expensive and/or cumbersome. Here we describe the use of thermography to read intradermal testing to detect peanut allergic sensitization in the murine model and as a first time sensitive tool for anaphylaxis stratification. The relative wheal size in the thermal image can be used to stratify anaphylaxis severity risk groups prior to a challenge. This screening method is nonlethal, inexpensive, minimally invasive and can be carried out expeditiously.

A case series: Association of anaphylaxis with a significant decrease in platelet levels and possible secondary risk of thrombosis: Anaphylaxis, Platelets, and Thrombosis

Anaphylaxis is a life threatening systemic inflammatory process that share mediators involved in the coagulation cascade. Platelet activating factor, known to increase platelet aggregation, has also been implicated as an important mediator of anaphylaxis. Although other inflammatory reactions are associated with an increased risk of thrombosis, anaphylaxis is currently not reported as one of them. Furthermore the role platelets may have in the perianaphylaxis period is not well understood. We here in present a retrospective case series of three patients that had platelet aberrations suggestive of PAF involvement and clinically significant thrombosis in close relationship with anaphylaxis.

Fenugreek Anaphylaxis in a Pediatric Patient

Fenugreek (Trigonella foenum-graecum) is a food product that belongs to the Leguminosae family along with other legumes. It has been used in India, Greece, and Egypt for culinary and medical purposes since ancient times, and today, fenugreek is used for flavoring foods, dyes, and drugs throughout the world. Many members of the Leguminosae family have been associated with allergies including soybean, green pea, and peanut. Fenugreek is also included in this family and may result in allergic reactions. Two cases of anaphylaxis have been described in children after ingestion of curry and pastes that contain fenugreek, although the true nature of the causative agent was unclear. We report the first case of fenugreek anaphylaxis in a pediatric patient defined by skin testing, immunoglobulin E ImmunoCAP assays, and clear ingestion.

Type 1 Kounis syndrome in a patient with idiopathic anaphylaxis.

Anaphylactic insults that cause cardiovascular signs and symptoms have been defined as Kounis syndrome, which has been associated with specific triggered anaphylactic reactions. Kounis syndrome has not been described in patients with no evidence of coronary artery disease (type I Kounis) in a scenario of idiopathic anaphylaxis. We reported a case of a 65-year-old white woman with no evidence of coronary artery disease who experienced two myocardial infarctions on separate occasions attributable to idiopathic anaphylaxis.

Idiopathic pancreatitis in a patient with a STAT3 mutation

Background Hyperimmunoglobulin E syndrome (HIES) is a rare primary immunodeficiency characterized by recurrent skin infections with abscesses, recurrent pneumonias with pneumatoceles, and immunoglobulin E levels of >10 times the upper limit of normal. Case The patient described herein had a classic case of signal transducer and activator of transcription S (STAT3) deficiency associated with HIES diagnosed several years before this particular presentation. He demonstrated extraimmune manifestations of the disease as well, including characteristic facies and a history of skeletal fractures. In addition, the patient had several distinct episodes of idiopathic pancreatitis for which a full gastrointestinal workup had been performed. STAT3 mutation was confirmed by genotyping at the time of diagnosis of HIES. Conclusions STAT3, a mammalian protein that regulates cell growth, survival, and differentiation, has been linked to human pancreatic carcinogenesis as well as the above-mentioned immune deficiency. Mouse studies demonstrated that genetic ablation of STAT3 exacerbates the course of acute pancreatitis, whereas normal pancreatic STAT3 seems to have a protective effect against necrotizing pancreatitis. An association between STAT3 mutations and pancreatitis has not yet been revealed in humans. Here we describe a case of acute pancreatitis that presented in a patient with STAT3 mutation.