Seeking Relevant Biomarkers in Common Variable Immunodeficiency

Abstract

Common variable immunodeficiency (CVID) is the most common symptomatic form of primary immunodeficiency. More than 50% of patients in some series suffer from autoimmune or inflammatory complications (the “CVID+” phenotype), and these are not adequately addressed by current treatments. Despite major advancements in genetics, the pathogenesis of the CVID+ phenotype has remained unexplained for most patients, necessitating the need for relevant biomarkers in both the clinic and research settings. In the clinics, reduced isotype-switched memory B cells (≤ 0.55% of B cells) and reduced T cells (CD4) can be utilized to identify those with increased complication risks. Additionally, condition-specific markers have also been suggested for lymphoma (normal or elevated IgM) and progressive interstitial lung disease (increased BAFF, normal or elevated IgM). Additional biomarkers have provided insights into disease pathogenesis, demonstrating wider systemic inflammation (increased LBP, sCD14, and sCD25; expanded ILC3), mucosal defects (increased zonulin, I-FABP), and perhaps reduced anti-inflammatory capability (reduced HDL) in CVID. Most recently, efforts have revealed elevated circulating bioactive bacterial DNA levels – marking microbial translocation and potentially linking the causation of multiple inflammatory changes previously observed in CVID. The implementation of high throughput profiling techniques may accelerate the search of relevant biomarker profiles in CVID and lead to better clinical risk stratification, revealing disease insights, and identifying potential therapeutic targets.

Genetics and clinical phenotypes in common variable immunodeficiency

“…One of the clinical features of the CVID syndrome that has emerged is that about half of these patients have infections as the central manifestation, which can be successfully treated or prevented with antibiotics and immunoglobulins. However, the others also have various apparently non-infectious, autoimmune, autoinflammatory, neoplastic and/or lymphoproliferative manifestations, often associated with systemic immune activation ( Wehr et al, 2008 ; Resnick et al, 2012b ; Cols et al, 2016 ; Smith and Cunningham-Rundles, 2021 ; Ho and Cunningham-Rundles, 2022 ). Patients in the second group often have autoimmune or inflammatory features as the initial presentation and primary clinical manifestation, with less obvious susceptibility to significant infectious diseases; these subjects also have increased morbidity and mortality as compared to those with the infection-only phenotype ( Chapel et al, 2008 ; Resnick et al, 2012a ).…”

“…A number of studies have probed reasons for the striking heterogeneity of this CVID patient pool ( Wehr et al, 2008 ; Chapel and Cunningham-Rundles, 2009 ; Resnick et al, 2012a ). These studies have sought biomarkers to identify these subjects, preferably at the time of diagnosis ( Ho and Cunningham-Rundles, 2022 ). Some of these markers include identification of subjects with loss of peripheral isotype switched memory B cells, increased CD21 low B cells (<10%), and/or reduced numbers of T cells, especially naïve CD4 T cells ( Warnatz et al, 2002 ; Fevang et al, 2007 ; Sanchez-Ramon et al, 2008 ; Wehr et al, 2008 ; Malphettes et al, 2009 ; Mouillot et al, 2010 ).…”

The Scope and Impact of Viral Infections in Common Variable Immunodeficiency (CVID) and CVID-like Disorders: A Literature Review

“…Over half of CVID patients—the so-called ‘CVID+’ cohort—suffer from inflammatory and/or autoimmune complications, with autoimmunity alone reported in around one quarter of individuals [ 43 , 44 , 45 ]. Regarding autoimmune complications, the role of regulatory immune cells, including CD4 regulatory T cells (CD4 Tregs) and the more newly described CD8 regulatory T cells (CD8 Tregs) and B regulatory cells (Bregs) and T follicular helper regulatory T cells (T FR ), have become targets for investigation [ 43 , 44 , 46 ].…”

“…Investigations into the CVID+ phenotype have suggested commensal bacteria and microbial translocation could be driving a state of immune activation, contributing to inflammatory and autoimmune complications [ 45 ]. Indeed, there is evidence of increased markers of bacterial infection, less diverse microbiomes, and significantly raised serum bacterial 16S rDNA levels, in CVID+ patients [ 45 ].…”

“…Investigations into the CVID+ phenotype have suggested commensal bacteria and microbial translocation could be driving a state of immune activation, contributing to inflammatory and autoimmune complications [ 45 ]. Indeed, there is evidence of increased markers of bacterial infection, less diverse microbiomes, and significantly raised serum bacterial 16S rDNA levels, in CVID+ patients [ 45 ]. These results speak to the complexity CVID, where disease manifestations potentially arise as an indirect result of the underlying immunodeficiency, and dysfunctional host-pathogen mechanisms.…”