BACKGROUND: Autoimmune cytopenias (AICs) regularly occur in profoundly IgG-deficient patients with common variable immunodeficiency (CVID). The isotypes, antigenic targets, and origin(s) of their disease-causing autoantibodies are unclear.
OBJECTIVE: We sought to determine reactivity, clonality, and provenance of AIC-associated IgM autoantibodies in patients with CVID.
METHODS: We used glycan arrays, patient erythrocytes, and platelets to determine targets of CVID IgM autoantibodies. Glycan-binding profiles were used to identify autoreactive clones across B-cell subsets, specifically circulating marginal zone (MZ) B cells, for sorting and IGH sequencing. The locations, transcriptomes, and responses of tonsillar MZ B cells to different TH- cell subsets were determined by confocal microscopy, RNA-sequencing, and cocultures, respectively.
RESULTS: Autoreactive IgM coated erythrocytes and platelets from many CVID patients with AICs (CVID+AIC). On glycan arrays, CVID+AIC plasma IgM narrowly recognized erythrocytic i antigens and platelet i-related antigens and failed to bind hundreds of pathogen- and tumor-associated carbohydrates. Polyclonal i antigen-recognizing B-cell receptors were highly enriched among CVID+AIC circulating MZ B cells. Within tonsillar tissues, MZ B cells secreted copious IgM when activated by the combination of IL-10 and IL-21 or when cultured with IL-10/IL-21-secreting FOXP3-CD25hi T follicular helper (Tfh) cells. In lymph nodes from immunocompetent controls, MZ B cells, plentiful FOXP3+ regulatory T cells, and rare FOXP3-CD25+ cells that represented likely CD25hi Tfh cells all localized outside of germinal centers. In CVID+AIC lymph nodes, cellular positions were similar but CD25hi Tfh cells greatly outnumbered regulatory cells.
CONCLUSIONS: Our findings indicate that glycan-reactive IgM autoantibodies produced outside of germinal centers may contribute to the autoimmune pathogenesis of CVID.

Common variable immunodeficiency (CVID) is an immune defect characterized by hypogammaglobulinemia and impaired development of B cells into plasma cells. As follicular helper T cells (TFH) play a central role in humoral immunity, we examined TFH cells in CVID, and investigated whether an inducible T cell co-stimulator (ICOS) agonist, vopratelimab, could modulate TFH, B cell interactions and enhance immunoglobulin production. CVID subjects had decreased TFH17 and increased TFH1 subsets; this was associated with increased transitional B cells and decreased IgG+ B and IgD-IgM-CD27+ memory B cells. ICOS expression on CVID CD4+ T cells was also decreased. However, ICOS activation of CD4+ T cells by vopratelimab significantly increased total CVID TFH, TFH2, cell numbers, as well as IL-4, IL-10 and IL-21 secretion in vitro. Vopratelimab treatment also increased plasma cells, IgG+ B cells, reduced naïve & transitional B cells and significantly increased IgG1 secretion by CVID B cells. Interestingly, vopratelimab treatment also restored IgA secretion in PBMCs from several CVID patients who had a complete lack of endogenous serum IgA. Our data demonstrate the potential of TFH modulation in restoring TFH and enhancing B cell maturation in CVID. The effects of an ICOS agonist in antibody defects warrants further investigation. This biologic may also be of therapeutic interest in other clinical settings of antibody deficiency.

Predominantly antibody deficiency (PAD) is associated with noninfectious inflammatory gastrointestinal disease. Population estimates of celiac disease (CeD) risk in those with PAD are limited.
To estimate population risk of PAD in individuals with CeD.
We conducted a nationwide case-control study in Swedish individuals who received a diagnosis of CeD between 1997 and 2017 (n = 34,980), matched to population comparators by age, sex, calendar year, and county. The CeD was confirmed through the Epidemiology Strengthened by histopathology Reports in Sweden study, which provided information on biopsy specimens from each of Sweden\'s pathology departments. PAD was identified using International Classification of Diseases, 10th Revision coding and categorized according to the International Union of Immunologic Societies. Logistic regression was used to calculate adjusted odds ratios (aORs) and 95% CIs.
PAD was more prevalent in CeD than in population controls (n = 105 [0.3%] vs n = 57 [0.033%], respectively). This translated to an aOR of 8.23 (95% CI 5.95-11.48). The association was strongest with common variable immunodeficiency (aOR 17.25; 95% CI 6.86-52.40), and slightly lower in other PAD (aOR 8.39; 95% CI 5.79-12.32). The risk of CeD remained increased at least 5 years after diagnosis of PAD (aOR 4.79; 95% CI 2.89-7.97, P-heterogeneity ≤ 0.001).
PAD was associated with an increased risk of CeD. A particularly strong association was seen in those with CVID, although this should be interpreted cautiously given the limited understanding of the mechanisms of histopathologic changes in these patients.

Activated phosphoinositide 3-kinase delta syndrome (APDS) is a rare genetic disorder that presents clinically as a primary immunodeficiency. Clinical presentation of APDS includes severe, recurrent infections, lymphoproliferation, lymphoma, and other cancers, autoimmunity and enteropathy. Autosomal dominant variants in two independent genes have been demonstrated to cause APDS. Pathogenic variants in PIK3CD and PIK3R1, both of which encode components of the PI3-kinase, have been identified in subjects with APDS. APDS1 is caused by gain of function variants in the PIK3CD gene, while loss of function variants in PIK3R1 have been reported to cause APDS2. We conducted a review of the medical literature and identified 256 individuals who had a molecular diagnosis for APDS as well as age at last report; 193 individuals with APDS1 and 63 with APDS2. Despite available treatments, survival for individuals with APDS appears to be shortened from the average lifespan. A Kaplan-Meier survival analysis for APDS showed the conditional survival rate at the age of 20 years was 87%, age of 30 years was 74%, and ages of 40 and 50 years were 68%. Review of causes of death showed that the most common cause of death was lymphoma, followed by complications from HSCT. The overall mortality rate for HSCT in APDS1 and APDS2 cases was 15.6%, while the mortality rate for lymphoma was 47.6%. This survival and mortality data illustrate that new treatments are needed to mitigate the risk of death from lymphoma and other cancers as well as infection. These analyses based on real-world evidence gathered from the medical literature comprise the largest study of survival and mortality for APDS to date.

Common variable immunodeficiency (CVID) is a heterogenous disease category created to distinguish late-onset antibody deficiencies from early-onset diseases like agammaglobulinemia or more expansively dysfunctional combined immunodeficiencies. Opinions vary on which affected patients should receive a CVID diagnosis which confuses clinicians and erects reproducibility barriers for researchers. Most experts agree that CVID\'s most indeliable feature is defective germinal center (GC) production of isotype-switched, affinity-maturated antibodies. Here, we review the biological factors contributing to CVID-associated GC dysfunction including genetic, epigenetic, tolerogenic, microbiome, and regulatory abnormalities. We also discuss the consequences of these biological phenomena to the development of non-infectious disease complications. Finally, we opine on topics and lines of investigation we think hold promise for expanding our mechanistic understanding of this protean condition and for improving the lives of affected patients.

Primary immune deficiency (PID) is a large group of diseases characterized by defective immune function, leading to recurrent infections, and immune dysregulation. Clinical presentations, severity, and complications differ for each disease, based on the components of the immune system that are impacted. When patients with PID present with respiratory symptoms, infections should be initially suspected, investigated, and promptly managed. However, non-infectious complications of PID also frequently occur and can lead to significant morbidity and mortality. They can involve both the upper and lower respiratory systems, resulting in various presentations that mimic infectious diseases. Thus, clinicians should be able to detect these conditions and make an appropriate referral to an immunologist and a pulmonologist for further management. In this article, we use case-based scenarios to review the differential diagnosis, investigation, and multidisciplinary treatment of non-infectious pulmonary complications in patients with primary immune deficiencies.

UNASSIGNED: Both primary (e.g. common variable immune deficiency, CVID) and secondary immune deficiency as well as multiple myeloma (MM) require medical intervention and treatment delay can exacerbate morbidity. This study investigated the potential importance of low levels of calculated globulin to detect immune deficiency and MM associated with immunoparesis (light chain, non-secretory MM).
UNASSIGNED: One hundred and thirty-nine patient serum samples from community physicians and outpatient clinics for liver function tests with low calculated globulin (<16 g/L, RR 18-37 g/L) levels were screened for immunoglobulins and protein electrophoresis. Further, 110 patients with globulin levels ≤16 g/L with screening for immunoglobulin levels and protein electrophoresis, requested through routine clinical care, were included in the analysis.
UNASSIGNED: Approximately 47% of patients in this cohort had secondary antibody deficiency as a result of hematological malignancy. Secondary iatrogenic (immunosuppressants, antiepileptic drugs) immune deficiency was detected in 20% of patients and a significant percentage of the patients were found by reflex testing at globulin levels <16 g/L. During the study period the screening detected new light chain and non-secretory MM in 2.2% of patients. Three patients with CVID and six patients with light chain myeloma were previously detected by screening, consequently alerting clinicians and reducing delay in treatment. A further 23% with several co-morbid conditions showed unexpected hypogammaglobulinemia; in this category, the study identified a subgroup that required further investigation.
UNASSIGNED: Investigation of low globulin levels detects patients with primary and secondary immune deficiency and MM. Optimizing treatment for decreased immunoglobulins in patients with other clinical co-morbidities may require increased clinician awareness and watchful clinical and laboratory assessment.

PURPOSE : Predominant antibody deficiency (PAD) disorders, including common variable immunodeficiency (CVID), have been linked to increased risk of gastrointestinal infections and inflammatory bowel diseases. However, there are limited data on the relationship between PAD, specifically CVID, and risk of microscopic colitis (MC).
We performed a nationwide case-control study of Swedish adults with MC diagnosed between 1997 and 2017 (n = 13,651). Data on biopsy-verified MC were retrieved from all of Sweden\'s pathology departments through the Epidemiology Strengthened by histoPathology Reports in Sweden (ESPRESSO) study. We defined predominant antibody deficiency using International Union of Immunologic Societies (IUIS) phenotypic classification. Individuals with MC were matched to population controls by age, sex, calendar year, and county. We used logistic regression to estimate adjusted odds ratios (aORs) and 95% confidence intervals (CIs).
The prevalence of PAD in MC was 0.4% as compared to 0.05% in controls. After adjustment for potential confounders, this corresponded to an aOR of 7.29 (95%CI 4.64-11.63). The magnitude of the association was higher for CVID (aOR 21.01, 95% 5.48-137.44) compared to other antibody deficiencies (aOR 6.16, 95% CI 3.79-10.14). In exploratory analyses, the association between PAD and MC was particularly strong among males (aOR 31.73, 95% CI 10.82-135.04).
In this population-based study, predominant antibody deficiency was associated with increased risk of MC, particularly among males. Clinicians who encounter these patients should consider a detailed infectious history and screening for antibody deficiency.

Chronic sleep issues can lead to poor quality of life and increased mortality and patients with chronic health conditions often report impaired sleep quality. Higher levels of fatigue have been identified in patients diagnosed with inborn errors of immunity (or primary immunodeficiency diseases). This research sought to better understand perceived sleep quality in individuals diagnosed with IEI.
A survey, which included the validated Sleep Quality Scale, was shared across multiple social media groups for individuals with a diagnosis of IEI.
Most of the participants were White/Caucasian females, between the ages of 30 and 74 years. The results of the Sleep Quality Scale suggest that this sample of individuals has moderate impairment of their sleep quality (71.8%), with a mean score of 43.0 (SD = 13.1). When comparing the results of the SQS to other patient populations and healthy control groups, the participants in this study had a poorer sleep quality score. Associations were identified between sleep quality and age, hours of sleep per night, time awake at night, times awake to urinate, attempted daytime naps, chronic pain, and mental health diagnoses.
This survey suggests that individuals with inborn errors of immunity have a moderate degree of perceived impairment in sleep quality. Healthcare providers are strongly encouraged to incorporate sleep quality screening in their routine assessments of patients with a diagnosis of Inborn Error of Immunity. Patients who are identified as having impaired sleep quality should be referred for further testing and interventions.

The association of immunocompromised patients and severity of COVID-19 infection is not well established. According to the Centers for Disease Control and Prevention (CDC), primary immune deficiencies (PIDs) are among the conditions that can predispose to a more severe course of COVID-19. We report the clinical course and immunological evaluation of five patients with common variable immune deficiency (CVID) who have experienced SARS-CoV-2 virus. Here we assess the severity of the infection, the immunophenotypic profile of the major lymphocyte subgroups, the nonspecific T-cell functional capacity and the SARS-CoV-2 specific effector T-cell immune response. Our results showed that the course of COVID-19 infection in CVID patients was mild to moderate and none of them developed a critical form of the disease. All patients developed a specific SARS-CoV-2 T cell immune response. Lymphopenia as well as impaired T-cell response prior to COVID-19 appeared to be related to a more severe course of the infection. Data on a good specific T cell response against SARS-CoV-2 in CVID patients will help to make the right vaccination decision and establish its efficacy. Clinical outcome even in these individual cases was in agreement with the therapeutic recommendations underlining that regular maintenance with subcutaneous immunoglobulins can be beneficial against immune system overreaction and a severe disease course and convalescent plasma is a treatment option in patients with CVID and COVID-19.