B Cells and Antibodies in Kawasaki Disease

The etiology of Kawasaki disease (KD), the leading cause of acquired heart disease in children, is currently unknown. Epidemiology supports a relationship of KD to an infectious disease. Several pathological mechanisms are being considered, including a superantigen response, direct invasion by an infectious etiology or an autoimmune phenomenon. Treating affected patients with intravenous immunoglobulin is effective at reducing the rates of coronary aneurysms. However, the role of B cells and antibodies in KD pathogenesis remains unclear. Murine models are not clear on the role for B cells and antibodies in pathogenesis. Studies on rare aneurysm specimens reveal plasma cell infiltrates. Antibodies generated from these aneurysmal plasma cell infiltrates showed cross-reaction to intracellular inclusions in the bronchial epithelium of a number of pathologic specimens from children with KD. These antibodies have not defined an etiology. Notably, a number of autoantibody responses have been reported in children with KD. Recent studies show acute B cell responses are similar in children with KD compared to children with infections, lending further support of an infectious disease cause of KD. Here, we will review and discuss the inconsistencies in the literature in relation to B cell responses, specific antibodies, and a potential role for humoral immunity in KD pathogenesis or diagnosis

Seasonal Testing, Results, and Effect of the Pandemic on Coxsackievirus Serum Studies

Coxsackieviruses (CVs) are common causes of infections and can be life-threatening. Unfortunately, rigorous studies guiding the clinician in interpreting CV serum antibody titer testing is lacking. To explore the epidemiology of circulating CVs and the serological test utility in aiding diagnosis of CV infections in our community, we obtained results of CV immunologic diagnostic tests between 2018 and 2022 from a regional healthcare database. For CV type A, rare individuals had positive CF (complement fixation) tests whereas all 16 individuals with IFA testing showed at least one positive serotype. For CV type B CF testing, 52.2% of 222 patients had at least one serotype positive, with B5 being most common and also the most common with higher titers (14.8% with ≥1:32). We found a significant reduction in seropositivity rate during the pandemic in 2020 compared to 2018, which continued through 2022 (OR: 0.2, 95% CI: 0.08–0.49, p-value < 0.001). During the pandemic, the seasonal pattern of positive tests varied from the pre-pandemic pattern. Testing for CVs was increased after the first year of the pandemic. Overall, the variability by month and seasonal change in our data support that CF testing can be used to identify recent CVB infection

COVID-19 in Newborns and Infants-Low Risk of Severe Disease: Silver Lining or Dark Cloud?

One hundred years after the 1918 influenza pandemic, we now face another pandemic with the severe acute respiratory syndrome-novel coronavirus-2 (SARS-CoV-2). There is considerable variability in the incidence of infection and severe disease following exposure to SARS-CoV-2. Data from China and the United States suggest a low prevalence of neonates, infants, and children, with those affected not suffering from severe disease. In this article, we speculate different theories why this novel agent is sparing neonates, infants, and young children. The low severity of SARS-CoV-2 infection in this population is associated with a high incidence of asymptomatic or mildly symptomatic infection making them efficient carriers. KEY POINTS: · There is a low prevalence of novel coronavirus disease in neonates, infants, and children.. · The fetal hemoglobin may play a protective role against coronavirus in neonates.. · Immature angiotensin converting enzyme (ACE2) interferes with coronavirus entry into the cells.

Decreased Clinical Severity of Pediatric Acute COVID-19 and MIS-C and Increase of Incidental Cases during the Omicron Wave in Comparison to the Delta Wave

This study describes differences in clinical presentation in hospitalized children with acute COVID-19 and MIS-C between the Delta and Omicron (BA.1.1) waves in a tertiary children’s hospital. This retrospective cohort study with case adjudication of hospitalized children with SARS-CoV-2-positive testing or MIS-C diagnosis occurred during the Delta and Omicron waves, from August 2021 until February 2022. There were no differences noted by race, but both waves disproportionally affected black children (24% and 25%). Assigned by a three-person expert panel, incidental diagnoses were higher in the Omicron wave (34% versus 19%). Hospitalization rates of non-incidental cases were higher during Omicron (3.8 versus 5.9 per 1000 PCR-positive community cases). Respiratory-related admissions were prominent during Delta, while Omicron clinical presentations varied, including a high number of cases of croup and seizures. Length of stay and ICU use during Omicron was significantly less than Delta for MIS-C and acute cases. Estimation of vaccination efficacy for preventing hospital admissions was 85.1–91.7% in the early Omicron period. Our estimates suggest that a protective role for vaccination continues into the Omicron wave. The high rate of incidental cases during the Omicron wave should be considered when reviewing more cursory summative data sets. This study emphasizes the need for continued clinical suspicion of COVID-19 even when lower respiratory symptoms are not dominant

Low frequency of broadly neutralizing HIV antibodies during chronic infection even in quaternary epitope targeting antibodies containing large numbers of somatic mutations

Neutralizing antibodies (Abs) are thought to be a critical component of an appropriate HIV vaccine response. It has been proposed that Abs recognizing conformationally dependent quaternary epitopes on the HIV envelope (Env) trimer may be necessary to neutralize diverse HIV strains. A number of recently described broadly neutralizing monoclonal Abs (mAbs) recognize complex and quaternary epitopes. Generally, many such Abs exhibit extensive numbers of somatic mutations and unique structural characteristics. We sought to characterize the native antibody (Ab) response against circulating HIV focusing on such conformational responses, without a prior selection based on neutralization. Using a capture system based on VLPs incorporating cleaved envelope protein, we identified a selection of B cells that produce quaternary epitope targeting Abs (QtAbs). Similar to a number of broadly neutralizing Abs, the Ab genes encoding these QtAbs showed extensive numbers of somatic mutations. However, when expressed as recombinant molecules, these Abs failed to neutralize virus or mediate ADCVI activity. Molecular analysis showed unusually high numbers of mutations in the Ab heavy chain framework 3 region of the variable genes. The analysis suggests that large numbers of somatic mutations occur in Ab genes encoding HIV Abs in chronically infected individuals in a non-directed, stochastic, manner

Association of VH4-59 Antibody Variable Gene Usage with Recognition of an Immunodominant Epitope on the HIV-1 Gag Protein

The human antibody response against HIV-1 infection recognizes diverse antigenic subunits of the virion, and includes a high level of antibodies to the Gag protein. We report here the isolation and characterization of a subset of Gag-specific human monoclonal antibodies (mAbs) that were prevalent in the antibody repertoire of an HIV-infected individual. Several lineages of Gag-specifc mAbs were encoded by a single antibody heavy chain variable region, VH4-59, and a representative antibody from this group designated mAb 3E4 recognized a linear epitope on the globular head of the p17 subunit of Gag. We found no evidence that mAb 3E4 exhibited any function in laboratory studies aimed at elucidating the immunologic activity, including assays for neutralization, Ab-dependent cell-mediated virus inhibition, or enhanced T cell reactivity caused by Gag-3E4 complexes. The findings suggest this immunodominant epitope in Gag protein, which is associated with VH4-59 germline gene usage, may induce a high level of B cells that encode binding but non-functional antibodies that occupy significant repertoire space following HIV infection. The studies define an additional specific molecular mechanism in the immune distraction activity of the HIV virion

Low frequency of broadly neutralizing HIV antibodies during chronic infection even in quaternary epitope targeting antibodies containing large numbers of somatic mutations

Neutralizing antibodies (Abs) are thought to be a critical component of an appropriate HIV vaccine response. It has been proposed that Abs recognizing conformationally dependent quaternary epitopes on the HIV envelope (Env) trimer may be necessary to neutralize diverse HIV strains. A number of recently described broadly neutralizing monoclonal Abs (mAbs) recognize complex and quaternary epitopes. Generally, many such Abs exhibit extensive numbers of somatic mutations and unique structural characteristics. We sought to characterize the native antibody (Ab) response against circulating HIV focusing on such conformational responses, without a prior selection based on neutralization. Using a capture system based on VLPs incorporating cleaved envelope protein, we identified a selection of B cells that produce quaternary epitope targeting Abs (QtAbs). Similar to a number of broadly neutralizing Abs, the Ab genes encoding these QtAbs showed extensive numbers of somatic mutations. However, when expressed as recombinant molecules, these Abs failed to neutralize virus or mediate ADCVI activity. Molecular analysis showed unusually high numbers of mutations in the Ab heavy chain framework 3 region of the variable genes. The analysis suggests that large numbers of somatic mutations occur in Ab genes encoding HIV Abs in chronically infected individuals in a non-directed, stochastic, manner

Heavy chain amino acid sequence alignment of V_H4-59 encoded mAbs.

<p>The heavy chain amino acid sequence of HIV-specific V_H4-59 encoded mAbs are shown aligned to the V_H4-59 germline gene. Conservation with the germline gene sequence is indicated by a <b>*</b> symbol in the alignments.</p

Heavy chain gene analysis of Gag-only VLP binding antibodies.

<p>Heavy chain gene analysis of Gag-only VLP binding antibodies.</p

Mapping the mAb 3E4 epitope on the surface of HIV Gag protein.

<p><b>(A)</b> Binding of mAb 3E4 to overlapping linear peptides of the HIV-1 Gag protein. <b>(B)</b> Structural depiction of the mAb 3E4 epitope (shown in red) on the HIV-1 Gag protein. <b>(C)</b> Structural depiction of deletion mutants #1, #3, #4, #5, #6, and #7 (shown in blue, yellow, magenta, cyan, orange or wheat) on the surface of the HIV-1 Gag protein. <b>(D)</b> Western blot analysis of Gag, wild-type Matrix protein, or each of 10 different Matrix protein deletion mutants, using mAb 3E4 as a probe.</p