Gastrointestinal Manifestations in X-linked Agammaglobulinemia

Abstract

Purpose X-linked agammaglobulinemia is a primary humoral immunodeficiency characterized by hypogammaglobulinemia and increased susceptibility to infection. Although there is increased awareness of autoimmune and inflammatory complications in XLA, the spectrum of gastrointestinal manifestations has not previously been fully explored. Methods We present a case report of a family with two affected patients with XLA. Given the gastrointestinal involvement of the grandfather in this family, we performed a retrospective descriptive analysis of XLA patients with reported diagnoses of GI manifestations and inflammatory bowel disease (IBD) or enteritis registered at the USIDNet, a national registry of primary immunodeficiencies. Results In this cohort of patients with XLA, we found that up to 35% had concurrent gastrointestinal manifestations, and 10% had reported diagnoses of IBD or enteritis. The most commonly reported mutations were missense, which have been associated with a less severe XLA phenotype in the literature. The severity of symptoms were wide-ranging, and management strategies were diverse and mainly experimental. Conclusions Patients with XLA may require close monitoring with particular attention for GI manifestations including IBD and infectious enteritis. Further studies are needed to improve diagnosis and management of GI conditions in XLA patients.

Bruton tyrosine kinase deficiency augments NLRP3 inflammasome activation and causes IL-1β–mediated colitis

“…Overall, our studies suggest that the activation of BTK in macrophages and DCs by TLR ligands or other primary activation factors serves as a physiologic mechanism of NLRP3 inflammasome regulation, in that BTK activation blocks the NLRP3 activation of the NLRP3 inflammasome in the absence of a costimulator. In addition, our findings provide an explanation for the fact that patients with XLA lacking functional BTK are prone to develop intestinal abnormalities (13).…”

“…The above studies of the relation of BTK expression to NLRP3 inflammasome-induced inflammation has several clinical ramifications. First, it provides an explanation for the observation that approximately one-third of patients with XLA have gastrointestinal abnormalities and approximately one-tenth of these patients have Crohn's disease (13). Second, patients with CLL being treated with ibrutinib frequently suffer from diarrhea (particularly early in the course of treatment), and it is reasonable to suggest that this may be related to increased gastrointestinal NLRP3 inflammasome activity arising from BTK inhibition by low concentrations of an inhibitor (38).…”

Recurrent and Sustained Viral Infections in Primary Immunodeficiencies

“…Chronic diarrhea (>6 weeks) is a frequent finding in PIDD patients. Given that the etiologies of chronic diarrhea in immunodeficient patients can be diverse, it is important to first distinguish if the diarrhea is infectious, malabsorptive, or inflammatory in nature as there are multiple types of PIDD that can present with autoimmune enteropathy or inflammatory bowel disease (94)(95)(96). PIDD patients are susceptible to multiple types of GI pathogens, and this section will focus on GI viruses.…”

Infection by Leishmania (Leishmania) infantum chagasi causes intestinal changes B‐1 cells dependent

“…The main role of B-1 in leishmaniasis is still controversial. 15,[17][18][19] B-1 cells deficiency has been described in the literature as having the potential of causing a series of immunological problems, such as low antibody production 34 and recurrent infections, 35 several gastrointestinal alterations and symptoms, 36 besides the worsening of visceral leishmaniasis. 25 Leishmania dissemination occurs via lymphatic or haematogenous circulation; the immune cells, such as dendritic cells, monocytes and macrophages, can participate in this transport.…”