The common variable immunodeficiency IgM repertoire narrowly recognizes erythrocyte and platelet glycans.

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.

Multisystem Inflammation and Organ Dysfunction After BNT162b2 Messenger RNA Coronavirus Disease 2019 Vaccination.

The U.S. Food and Drug Administration has to date granted approval or emergency use authorization to three vaccines against severe acute respiratory syndrome coronavirus 2 and coronavirus disease 2019. In clinical trials and real-use observational studies, the Pfizer-BioNTech BNT162b2 messenger RNA coronavirus disease 2019 vaccine, as well as the Moderna mRNA-1273 messenger RNA coronavirus disease 2019 vaccine, have demonstrated high efficacy and few adverse events. CASE SUMMARY: A 20-year-old male college student in good health developed tinnitus and hematuria shortly after vaccination and progressed swiftly to a syndrome of: systemic inflammation; acute kidney injury requiring hemodialysis; acute, bilateral, complete sensorineural hearing loss; radiographic evidence of acute multifocal ischemic strokes; pericardial effusion complicated by tamponade physiology requiring pericardial evacuation; pleural effusions requiring evacuation; and systemic capillary leak. An extensive clinical and research investigation, including cytokine analysis, whole blood cytometry by time of flight, and whole exome sequencing, did not reveal a definitive explanatory mechanism. CONCLUSION: While the overall safety profile of the BNT162b2 coronavirus disease 2019 vaccine remains excellent for the general population, rare serious events have been reported. In this report, we describe a case of multisystem inflammation and organ dysfunction of unknown mechanism beginning shortly after administration of the first dose of BNT162b2 coronavirus disease 2019 vaccine in a previously healthy recipient.

Common variable immunodeficiency-associated endotoxemia promotes early commitment to the T follicular lineage.

BACKGROUND: Although chiefly a B-lymphocyte disorder, several research groups have identified common variable immunodeficiency (CVID) subjects with numeric and/or functional TH cell alterations. The causes, interrelationships, and consequences of CVID-associated CD4+ T-cell derangements to hypogammaglobulinemia, autoantibody production, or both remain unclear. OBJECTIVE: We sought to determine how circulating CD4+ T cells are altered in CVID subjects with autoimmune cytopenias (AICs; CVID+AIC) and the causes of these derangements. METHODS: Using hypothesis-generating, high-dimensional single-cell analyses, we created comprehensive phenotypic maps of circulating CD4+ T cells. Differences between subject groups were confirmed in a large and genetically diverse cohort of CVID subjects (n = 69) by using flow cytometry, transcriptional profiling, multiplex cytokine/chemokine detection, and a suite of in vitro functional assays measuring naive T-cell differentiation, B-cell/T-cell cocultures, and regulatory T-cell suppression. RESULTS: Although CD4+ TH cell profiles from healthy donors and CVID subjects without AICs were virtually indistinguishable, T cells from CVID+AIC subjects exhibited follicular features as early as thymic egress. Follicular skewing correlated with IgA deficiency-associated endotoxemia and endotoxin-induced expression of activin A and inducible T-cell costimulator ligand. The resulting enlarged circulating follicular helper T-cell population from CVID+AIC subjects provided efficient help to receptive healthy donor B cells but not unresponsive CVID B cells. Despite this, circulating follicular helper T cells from CVID+AIC subjects exhibited aberrant transcriptional profiles and altered chemokine/cytokine receptor expression patterns that interfered with regulatory T-cell suppression assays and were associated with autoantibody production. CONCLUSIONS: Endotoxemia is associated with early commitment to the follicular T-cell lineage in IgA-deficient CVID subjects, particularly those with AICs.

Patients with common variable immunodeficiency with autoimmune cytopenias exhibit hyperplastic yet inefficient germinal center responses.

BACKGROUND: The lack of pathogen-protective, isotype-switched antibodies in patients with common variable immunodeficiency (CVID) suggests germinal center (GC) hypoplasia, yet a subset of patients with CVID is paradoxically affected by autoantibody-mediated autoimmune cytopenias (AICs) and lymphadenopathy. OBJECTIVE: We sought to compare the physical characteristics and immunologic output of GC responses in patients with CVID with AIC (CVID+AIC) and without AIC (CVID-AIC). METHODS: We analyzed GC size and shape in excisional lymph node biopsy specimens from 14 patients with CVID+AIC and 4 patients with CVID-AIC. Using paired peripheral blood samples, we determined how AICs specifically affected B-and T-cell compartments and antibody responses in patients with CVID. RESULTS: We found that patients with CVID+AIC displayed irregularly shaped hyperplastic GCs, whereas GCs were scarce and small in patients with CVID-AIC. GC hyperplasia was also evidenced by an increase in numbers of circulating follicular helper T cells, which correlated with decreased regulatory T-cell frequencies and function. In addition, patients with CVID+AIC had serum endotoxemia associated with a dearth of isotype-switched memory B cells that displayed significantly lower somatic hypermutation frequencies than their counterparts with CVID-AIC. Moreover, IgG+ B cells from patients with CVID+AIC expressed VH4-34-encoded antibodies with unmutated Ala-Val-Tyr and Asn-His-Ser motifs, which recognize both erythrocyte I/i self-antigens and commensal bacteria. CONCLUSIONS: Patients with CVID+AIC do not contain mucosal microbiota and exhibit hyperplastic yet inefficient GC responses that favor the production of untolerized IgG+ B-cell clones that recognize both commensal bacteria and hematopoietic I/i self-antigens.

The relationship between hypogammaglobulinemia, monoclonal gammopathy of undetermined significance and humoral immunodeficiency: a case series.

Hypogammaglobulinemia of the non-monoclonal immunoglobulin heavy chain classes has been reported in monoclonal gammopathy of undetermined significance (MGUS) patients. Whether low polyclonal immunoglobulin levels are associated with impaired specific antibody production and whether they represent a risk factor for the development of recurrent bacterial infections have not been established in this population. We determined the frequency of MGUS in patients referred to a tertiary care clinical immunology ambulatory care practice for evaluation of hypogammaglobulinemia, who were assessed for deficits in specific antibody production and the presence of recurrent infections. Of the 133 patients evaluated for hypogammaglobulinemia, 68 were screened for monoclonal gammopathy and 5 were found to have MGUS. Three had MGUS associated hypogammaglobulinemia in the absence of a defining primary immunodeficiency, one possibly had common variable immunodeficiency, and one had an uncertain diagnosis. Thus, MGUS may be uncovered in patients presenting with hypogammaglobulinemia even in those who lack an elevated serum level of IgG, IgM, or IgA.

The diagnosis and treatment of allergic rhinitis during pregnancy and lactation.

Rhinitis, including allergic rhinitis, in pregnancy represents a challenge to the physician in terms of its diagnosis and therapy. Although several unique in-fluences of pregnancy adversely affect nasal mucosa, there is growing recognition that most symptomatic nasal problems are expressions of diagnostic entities that have been or will be experienced by the patient in the nonpregnant state. In approaching gestational rhinitis, emphasis should be placed on making an early, accurate diagnosis so that limited, specific, and informed medicinal intervention can be used. Simultaneously, the physician should keep in mind that rhinosinusitis in pregnancy is not necessarily a benign clinical problem. It is important to remember that upper airway disease, if uncontrolled, has a significant adverse effect on quality of life and may exacerbate coexisting asthma, which could affect the pregnancy outcome adversely [82]. Specialty consultation with otolaryngology or allergy may be necessary in the symptomatic pregnant woman before an accurate diagnosis and successful therapeutic recommendations can be made. The medico-legal atmosphere in the United States poses problems in making clinical statements about the absolute safety of medicinal intervention during pregnancy. For physicians who choose to take up this therapeutic challenge,suitable pharmacologic agents are available to manage the pregnant patient who has rhinitis or rhinosinusitis to achieve the desired therapeutic outcome. Suggested guidelines for the treatment of allergic conjunctivitis and rhinitis are summarized in Box 2. In the individual clinical situation, management decisions must be made only after establishing an exact clinical diagnosis, giving full consideration to the therapeutic risks, benefits, and alternatives, and documenting this in the patient's record. Moreover, the physician's interpretation of the benefit-risk ratio and the therapeutic decisions based thereon must be fully explained to, and approved by, the pregnant patient before intervention is initiated.A significant number of women who suffer from rhinitis of pregnancy are allergic. Under these circumstances, the best first-line approach is avoidance of allergens, which can reduce symptoms significantly. Often, what is chosen first is either a medication or the decision to allow the pregnant patient to suffer the symptoms, which can affect the pregnancy outcome adversely. Limited allergy consultation can be useful under these circumstances to identify pertinent allergens and to direct avoidance effectively. If avoidance is unsuccessful, then,with the informed consent of the patient and documentation in the chart, medicinal intervention can begin as shown (see Box 2). Although many women and caregivers may choose not to intervene with medications based on fear of teratogenicity, such notions are contradicted by a significant amount of medical evidence. This is especially true of drug intervention for rhinitis and rhinosinusitis after the first trimester.

Clinical deterioration in pediatric asthmatic patients after September 11, 2001.

BACKGROUND: New York City residents were exposed to a variety of inhaled substances after the collapse of the World Trade Center. Exposure to these substances might lead to an increase in asthma severity, with residential distance from Ground Zero predictive of the degree of change. OBJECTIVE: We sought to assess the effect of the World Trade Center collapse on local pediatric asthmatic patients. METHODS: We retrospectively reviewed the charts of 205 pediatric patients with established asthma from a clinic in lower Manhattan's Chinatown. Clinical data were obtained for the year before and the year after September 11, 2001. Measurements included numbers of visits, asthma medication prescriptions, oral corticosteroid prescriptions, weekly doses of rescue inhaler, and peak expiratory flow rates. Residential zip codes were used to compare the asthma severity of patients living within and beyond a 5-mile radius of Ground Zero. RESULTS: After September 11, 2001, these children had more asthma-related clinic visits (P = .002) and received more prescriptions for asthma medications (P = .018). No significant differences in oral steroid or rescue inhaler use were noted. Those living within 5 miles had more clinic visits after September 11, 2001 (P = .013); the increase in clinic visits for patients living more than 5 miles from Ground Zero was not significant. Mean percent predicted peak expiratory flow rates decreased solely for those patients living within 5 miles of Ground Zero during the 3 months after September 11, 2001. CONCLUSIONS: Asthma severity worsened after September 11, 2001, in pediatric asthmatic patients living near Ground Zero. Residential proximity to Ground Zero was predictive of the degree of decrease in asthma health.