Lymphocytes Utilize Somatic Mutations, Epigenetic Silencing, and the Proteasome to Escape Truncated WASP Expression.

Wiskott-Aldrich Syndrome Protein (WASP) deficiency causes Wiskott-Aldrich Syndrome (WAS), a sex-linked disorder characterized by combined immunodeficiency, microthrombocytopenia, and eczema. Like WASP-deficient humans, WASP-deficient mice produce normal numbers of functionally defective T cells. Here, we report a WAS patient with a novel germline frameshifting WAS mutation encoding a truncated form of WASP lacking the C-terminal cofilin homology (C) and the acidic region (A) domains (WASPΔCA). Although stably overexpressed in embryonic kidney cell lines, WASPΔCA was undetectable in circulating patient leukocytes. Deep sequencing, transcript profiling, and protein degradation analyses demonstrated patient lymphocytes employ an array of genetic, epigenetic, and proteasomal strategies to avoid expressing WASPΔCA.

Immunoprofiles associated with controlled human malaria infection and naturally acquired immunity identify a shared IgA pre-erythrocytic immunoproteome.

Knowledge of the Plasmodium falciparum antigens that comprise the human liver stage immunoproteome is important for pre-erythrocytic vaccine development, but, compared with the erythrocytic stage immunoproteome, more challenging to classify. Previous studies of P. falciparum antibody responses report IgG and rarely IgA responses. We assessed IgG and IgA antibody responses in adult sera collected during two controlled human malaria infection (CHMI) studies in malaria-naïve volunteers and in 1- to 6-year-old malaria-exposed Malian children on a 251 P. falciparum antigen protein microarray. IgG profiles in the two CHMI groups were equivalent and differed from Malian children. IgA profiles were robust in the CHMI groups and a subset of Malian children. We describe immunoproteome differences in naïve vs. exposed individuals and report pre-erythrocytic proteins recognized by the immune system. IgA responses detected in this study expand the list of pre-erythrocytic antigens for further characterization as potential vaccine candidates.

Late-occurring infections in a contemporary cohort of hematopoietic cell transplantation survivors.

BACKGROUND: There is a paucity of studies describing the incidence and risk factors for late-occurring (≥1 year) infectious complications in contemporary survivors of hematopoietic cell transplantation (HCT). METHODS: This was a retrospective cohort study of 641 1-year survivors of HCT, transplanted between 2010 and 2013 as adults, and in remission from their primary disease. Standardized definitions were used to characterize viral, fungal, and bacterial infections. Cumulative incidence of infections was calculated, with relapse/progression considered as a competing risk event. Fine-Gray subdistribution hazard ratio estimates and 95% confidence intervals (CI) were obtained, adjusted for relevant covariates. RESULTS: Median age at HCT was 55.2 years (range 18.1-78.1 years); 54.0% were survivors of allogeneic HCT. The 5-year cumulative incidence of a late-occurring infection for the entire cohort was 31.6%; the incidence of polymicrobial (≥2) infections was 10.1%. In survivors who developed at least one infection, the 5-year incidence of a subsequent infection was 45.3%. Among allogeneic HCT survivors, patients with acute lymphoblastic (HR = 1.82 95% CI [1.12-2.96]) or myeloid (HR = 1.50 95% CI [1.02-2.20]) leukemia, and those with an elevated HCT-Comorbidity index score (HR = 1.09 95% CI [1.01-1.17]) were more likely to develop late-occurring infections; there was an incremental risk associated with severity of graft versus host disease (GVHD) at 1-year post-HCT (mild: HR = 2.17, 95% CI [1.09-4.33]; moderate/severe: HR = 3.78, 95% CI [1.90-7.53]; reference: no GVHD). CONCLUSIONS: The burden of late-occurring infections in HCT survivors is substantial, and there are important patient- and HCT-related modifiers of risk over time. These findings may help guide personalized screening and prevention strategies to improve outcomes after HCT.

Heterozygosity for CMT Type 4 Predicts a Severe Vincristine-induced Polyneuropathy Phenotype: A Case Report and Review of Literature.

Vincristine (VCR) is a common chemotherapeutic agent used in the treatment of multiple types of pediatric tumors. VCR's adverse effects are well documented and commonly involve peripheral neuropathy via axonal degeneration. Neuropathic severity is dose-dependent, with sensory deficits occurring with as little as 4 mg cumulative dose. Severe peripheral neuropathy is generally rare, but its effects become additive when given to patients with undiagnosed hereditary peripheral neuropathy such as Charcot-Marie-Tooth. We report a case of an effect of VCR administration given to a patient who developed grade 4 neuropathy and was found to be a carrier of Charcot-Marie-Tooth disease type 4.