Common Variable Immunodeficiency

Non-infectious complications in common variable immunodeficiency (CVID) have emerged as a major clinical challenge. Detailed clinical spectrum, organ-specific pathologies and associated sequelae from 623 CVID patients followed in New York since 1974 were analyzed, and recent insights to pathogenesis were reviewed. Non-infectious manifestations were present in 68.1% of patients, and they do not tend to be present in isolation. They include autoimmunity (33.2%), chronic lung disease (30.3%), lymphoid hyperplasia/splenomegaly (20.9%), liver disease (12.7%), granulomas (9.3%), gastrointestinal disease (7.3%), lymphoma (6.7%), and other malignancies (6.4%). In the lungs, interstitial disease and bronchiectasis were the most common findings, with lymphoma at this site being a rare (n = 6), but serious, manifestation. Bronchiectasis was not a prerequisite for the development of interstitial disease. In the liver, granulomas and nodular regenerative hyperplasia were the most common. Gastrointestinal disease may affect any segment of the intestinal tract, with lymphoid infiltrations and villous blunting being the leading histologic findings. With progression of organ-specific diseases, a wide spectrum of associated sequelae was observed. Lymphoma was more common in females (P = 0.036)-all B cell types except in one subject. Solid organ transplantations (liver, n = 5; lung, n = 4; combined lung and heart, n = 2) and hematopoietic stem cell transplantations (for B cell lymphoma, n = 1) have rarely been performed in this cohort, with mixed outcomes. Recent identification of monogenic defects, in ~10-30% of various CVID cohorts, has highlighted the molecular pathways that can affect both antibody production and broader immune regulation. In addition, cellular defects in both innate and adaptive immune systems are increasingly recognized in this syndrome.

Common variable immunodeficiency (CVID) is the most frequent symptomatic primary immunodeficiency characterized by recurrent infections, hypogammaglobulinemia and poor response to vaccines. Its diagnosis is made based on clinical and immunological criteria, after exclusion of other diseases that can cause similar phenotypes. Currently, less than 20% of cases of CVID have a known underlying genetic cause. We have analyzed whole-exome sequencing and copy number variants data of 36 children and adolescents diagnosed with CVID and healthy relatives to estimate the proportion of monogenic cases. We have replicated an association of CVID to p.C104R in TNFRSF13B and reported the second case of homozygous patient to date. Our results also identify five causative genetic variants in LRBA, CTLA4, NFKB1, and PIK3R1, as well as other very likely causative variants in PRKCD, MAPK8, or DOCK8 among others. We experimentally validate the effect of the LRBA stop-gain mutation which abolishes protein production and downregulates the expression of CTLA4, and of the frameshift indel in CTLA4 producing expression downregulation of the protein. Our results indicate a monogenic origin of at least 15-24% of the CVID cases included in the study. The proportion of monogenic patients seems to be lower in CVID than in other PID that have also been analyzed by whole exome or targeted gene panels sequencing. Regardless of the exact proportion of CVID monogenic cases, other genetic models have to be considered for CVID. We propose that because of its prevalence and other features as intermediate penetrancies and phenotypic variation within families, CVID could fit with other more complex genetic scenarios. In particular, in this work, we explore the possibility of CVID being originated by an oligogenic model with the presence of heterozygous mutations in interacting proteins or by the accumulation of detrimental variants in particular immunological pathways, as well as perform association tests to detect association with rare genetic functional variation in the CVID cohort compared to healthy controls.

The scaffold proteins CARMA1-3 (encoded by the genes CARD11, -14 and -10) and CARD9 play major roles in signaling downstream of receptors with immunoreceptor tyrosine activation motifs (ITAMs), G-protein coupled receptors (GPCR) and receptor tyrosine kinases (RTK). These receptors trigger the formation of oligomeric CARMA/CARD-BCL10-MALT1 (CBM) complexes via kinases of the PKC family. The CBM in turn regulates gene expression by the activation of NF-κB and AP-1 transcription factors and controls transcript stability. The paracaspase MALT1 is the only CBM component having an enzymatic (proteolytic) activity and has therefore recently gained attention as a potential drug target. Here we review recent advances in the understanding of the molecular function of the protease MALT1 and summarize how MALT1 scaffold and protease function contribute to the transmission of CBM signals. Finally, we will highlight how dysregulation of MALT1 function can cause pathologies such as immunodeficiency, autoimmunity, psoriasis, and cancer.

IntroductionUp to one-third of the patients diagnosed with common variable immunodeficiency (CVID) may develop gastrointestinal (GI) and hepatic manifestations. This study aimed to evaluate the prognostic significance of enteropathy and liver disease in patients with CVID.MethodsWe conducted a retrospective study including all consecutive adult patients with CVID followed in a tertiary care center in Spain from January 1990 to January 2023. A diagnosis of CVID-associated enteropathy (CVID-E) and CVID-associated liver involvement (CVID-L) was established when objective clinical, endoscopic, histologic, radiologic or hemodynamic findings were present. Relevant prognostic outcomes and their risk factors were studied, including survival, GI infections, and GI cancer.ResultsEighty-nine patients with confirmed CVID were included, 26 of them (29.2%) had CVID-E and 23 (25.8%) had CVID-L. Nineteen (73.1%) patients with CVID-E suffered from GI infections, while 12 (46.2%) presented concurrent liver involvement. In comparison with the rest of the cohort, patients with CVID-E had more frequently liver involvement, GI infections, and GI cancer. Multivariate analysis identified CVID-E as an independent risk factor for GI infections. Twelve (52.2%) patients with CVID-L concurrently exhibited CVID-E, and patients with CVID-L presented more CVID-E, splenomegaly, and a trend toward more GI cancer and GI infections. CVID-L and age at CVID diagnosis emerged as independent risk factors for mortality.DiscussionGI and hepatic involvements are common in patients with CVID and frequently occur together. These manifestations significantly affect the disease course, increasing the risk of GI infections, GI malignancy, and, in the case of liver disease, mortality.