The hallmarks of X-linked Agammaglobulinemia (XLA) are panhypogammaglobulinemia, absent B-cells, and recurrent sinopulmonary and gastrointestinal infections starting at an early age, as well as other infections like cellulitis, meningitis, arthritis and sepsis. A number of non-infectious complications have been reported in these patients, including autoimmune diseases and malignancy, especially lymphomas. Here, we report the case of a 30-year old man who developed gastric adenocarcinoma in the context of XLA. Previous reports of, and hypotheses addressing the development of cancer in patients with XLA, are also summarized. Solid cancer in XLA affects mainly the gastrointestinal tract and seems to be related to chronic infection. A natural evolution can be traced back from gastric adenocarcinoma to megaloblastic anemia due to achlorhydria in the context of chronic infection; periodic endoscopy thus seems justified to detect and treat carcinoma in early stages.

Introduction: Around 20% of all inborn errors of immunity (IEI) are autosomal dominant or monoallelic, either by haploinsufficiency, negative dominance, or gain of function (GOF). GOF phenotypes usually include autoinflammation, autoimmunity, lymphoproliferation, allergies, and some infections. Case series: We describe the cases of two unrelated patients born of HIV-seroconcordant parents. Both patients are HIV-negative but carry de novo GOF missense variants that resulted in inflammatory lymphoproliferative IEI diseases: signal transducer and activator of transcription 3 (STAT3)-GOF and phosphatidylinositol 3-kinase, catalytic delta (PIK3CD)-GOF. Both variants were found through whole-exome sequencing and confirmed by Sanger. An 11-year-old male with recurrent sinopulmonary infections, dysmorphism, growth delay, bronchiectasis, and mild mental retardation, as well as lymphopenia, thrombocytopenia, and high immunoglobulin M. Both his parents were known to be HIV-positive under anti-retroviral treatment. HIV infection was repeatedly ruled out in the patient, whom through whole-exome sequencing was found to have a heterozygous missense variant in exon 24 of PIK3CD, a hotspot transition, and the most reported variant in PIK3CD-GOF patients. A 6-year-old male with autoimmune hemolytic anemia, lymphoproliferation, short stature, and intractable diarrhea. Both his parents were found to be HIV-positive. HIV was repeatedly ruled out in the patient by ELISA and viral load. He was found to have a heterozygous missense/splice variant in exon 22 of STAT3, a hotspot transition, and the most reported variant in STAT3-GOF patients. Discussion: The AID/APOBEC3 A-H family of proteins are cytidine deaminases that induce G>A hypermutation in both the invading viral DNA and the host genome, which results in stop codons inside the endogenized retroviral sequence. Both variants found in our patients are G to A transitions. Retroviral infection might thus have resulted in host genome instability, and our patients’ rare congenital diseases are the unfortunate consequence of somatic hypermutation in one of their parents’ gametes.

BackgroundCommon variable immunodeficiency (CVID) is a primary antibody deficiency characterized by a decrease in antibody production and low or normal B cell numbers. To elucidate the clinical and immunological heterogeneity of this condition, we studied 13 patients diagnosed with CVID, examined the status of B-cell maturation in patients with CVID by analyzing IgD/CD27 expression, and we analyze the in vitro B cell differentiation to plasma cells.MethodsT, B and NK cell populations was analyzed by flow citometry, expression of CD27 marker was determined to define B cell subsets; we also assessed molecules important for B cell proliferation and differentiation, such as TNFRSF13B (TACI), inducible costimulator (ICOS), CD154, CD20, ICOSL and BAFFR. For B cell differentiation assays, total PBMCs were cultured with CpG alone, or with SAC Cowan, Pokweed and CpG; flow cytometric analysis of plasmablast generation was perfomed after 7 days of culture.ResultsReduced numbers of T and B cells was observed in CVID patients, this reduction was more prominent in adults than in children. One group of 8 patients showed a significant reduction in IgD+CD27+ memory B cells while 3 patients had similar percentage than the healthy control group. The IgD-CD27+ memory B cell population was low in 10 patients (<12%); while it was similar to the healthy control group in 2 of the patients. BAFFR expression in B cells was reduced in 4 patients. Finally, the differentiation to plasmablasts was reduced in patients, stimulation with CpG induced 18.5% of plasmablasts (SD = 12.5%) whereas it was 24% (SD = 8.3%) in healthy controls.ConclusionsThese results suggest that a combined defect in T and B cells may account for CVID, at least in some patients. On the other hand, the complete analysis of markers important for B proliferation and differentiation such as ICOS, CD40, CD154 and TACI can be a useful tool for understanding this heterogeneous disease. B cells from CVID patients fail to progress to IgD-CD27+ memory B cells and plasmablasts. Based on these facts, we hypothesize that one or more crucial signaling molecules is required to induce terminal differentiation into memory B cells, if defective, may cause CVID.

BackgroundX-linked agammaglobulinemia (XLA) is characterized by impaired B-cell differentiation caused by mutations in Bruton's tyrosine kinase (Btk) gen. Btk is expressed in myeloid cells and recent evidence support that it participates in Toll like receptor signaling, but results regarding its rol in XLA patients are contradictories.ObjectiveTo evaluate lipopolysaccharide (LPS)-induced pro-inflammatory cytokine response in peripheral blood mononuclear cells (PBMC) from XLA patients.MethodsThirteen patients with XLA were included in the study. PBMC LPS-induced TNF-α, IL-1β, IL-6, and IL-10 production was determined by ELISA and compared with that obtained from matched healthy controls. Cytokine production was correlated with the severity of the mutation, affected domain and clinical characteristics.ResultsIn response to LPS, PBMC from XLA patients produced significantly higher amounts of pro-inflammatory cytokines and IL-10 compared with controls and this production is not influenced by the neither severity of mutation or the affected domain. PBMC from patients with a history of more hospital admissions before diagnosis and patients with lower expression of Btk in monocytes produced higher levels of TNF-α and IL-1β, respectively. PBMC from patients with lower IgA levels showed a higher production of TNF-α and IL-1β. Less severe (punctual) mutations in Btk gene were associated with higher IgG levels at diagnosis.ConclusionsOur results demonstrated a predominantly inflammatory response in XLA patients after LPS stimuli and suggest a TLR signaling dysregulation in absence of Btk. This response may be influenced by environmental factors.