This Research Topic is the second volume of the “SARS-CoV-2 Variants, B Lymphocytes, and Autoreactivity” Community Series. Please see Volume I here

Immune profiling of COVID-19 patients revealed that infection with SARS-CoV2 is associated with a variety of changes in circulating B cell populations, including naïve B cells, transitional B cells, plasmablasts, plasma cells, class-switched and unswitched memory B cells, T-bet+ B cells, CD27-IgD- double-negative B cells, and “innate-like” B cells. Molecular characterization of the antibodies produced against SARS-CoV-2 indicated a variety of characteristics, including elongated CDR3 sequences with hydrophobic amino acids, a low mutation rate in their heavy-chain variable region genes, or an accumulation of somatic mutations in SARS-CoV-2- specific memory B cells over time, typical of antigen-driven B cell responses.

In the microanatomical environments of COVID-19 patients, deficits in germinal center formation have been reported in the spleen and thoracic lymph nodes analyzed post-mortem, suggesting the generation of plasma cells through a thymus-independent B cell activation process that leads to a low level of somatic mutations. There is, however, evidence for the accumulation of somatic mutations in SARS-CoV-2-specific B cells, a hallmark of germinal center-dependent B cell responses that contrasts with the involvement of an early extrafollicular immune response driven by SARS-CoV-2. On the other hand, clinical observations indicate that COVID-19 is associated with auto-inflammatory disorders, including autoimmune cytopenia, Guillain-Barre syndrome, Kawasaki disease, and anti-phospholipid syndrome. Additionally, a proportion of anti-SARS-CoV-2 antibodies bind to epitopes expressed in brain-, lung-, heart-, kidney-, or gut-tissue. Intriguingly, a subset of patients with life-threatening COVID-19 pneumonia have autoantibodies against interferon and related cytokines. The mechanisms responsible for tissue damage are not completely understood, but it remains possible that self-reactive antibodies could contribute to certain clinical symptoms during COVID-19.

Recent studies confirmed that SARS-CoV-2 continues to give rise to genetic changes and field variants with increased potential to evade the activity of memory B cells and enhance viral transmission and/or pathogenicity. Several reports suggest the existence of a potential risk of re-infection in subjects who have developed a mild form of COVID-19. Consequently, vaccination against the SARS-CoV-2 and its variants is likely to have a temporary lasting protective effect, implying a need for periodic vaccinations against new emerging variants. Therefore, a better understanding of the consequences of the impact of these escape variations on the B cell compartment could allow the development of new vaccine formulations that incorporate the mutations identified.

In a series of Original Research, General Commentary, Review, and Mini Review articles, this Research Topic aims to provide an overview and stimulate discussions of the impact of these escape variations on the B cell compartment with regard to the emergence of autoreactivity and development of new vaccine formulations. We hope for a robust and critical assessment of adaptable immune tolerance mechanisms in individuals with various predisposing conditions and of different gender and age. Specific themes to be addressed include, but are not limited to:

- Dissection of the B cell repertoire expressed at different stages of infection

- Adaptive value of somatic and junctional mechanisms in B cell repertoire formation

- Distribution of the repertoire of tissue-resident B cell clones, i.e. the lung, during disease progression

- Mechanisms governing the germinal center-dependent anti-SARS-CoV-2 immune response and the extrafollicular pathway

- Mathways that may impede affinity-maturation and formation of memory B cells during COVID-19

- Studies of the origin, magnitude, and stability of humoral response to SARS-CoV-2 genetic variants

- Determination of the long-term duration of potentially protective memory B cells in patients infected with the virus and in vaccinees

- Comprehensive picture of anti-SARS-CoV-2 B cell memory to SARS-CoV-2 variants

- Role of cross-reactive B cells in shaping the SARS-CoV-2 memory response in recovered individuals

- Impact of ventilatory parameters, such as respiratory rate, SpO2, and PaO2/FiO2, on changes of memory B cells and disease severity scores

- Site of emergence of autoreactive B cells and their pathogenic role in COVID-19

- Fate of autoreactive B cell responses after resolution of SARS-CoV-2 infection

- Potential pathogenic role of autoreactive B cells in COVID-19

- Possible protective role of autoreactive antibodies in COVID-19

- Contribution of B cell tolerance mechanisms to the course and severity of COVID-19

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