The Role of Extrafollicular B Cells in Tissue Inflammation and Fibrosis: Insights from COVID-19 and IgG4-Related Disease


The interaction between T and B cells in secondary lymphoid organs plays a crucial role in immune responses. However, in the context of antigen overload and dysregulated inflammation, these T-B interactions may favor extrafollicular over germinal center responses.

Extrafollicular B cell populations that arise in a disease-specific manner have been implicated in disease progression and sequelae. Notably, in COVID-19 patients, subsets of antigen-specific disease-related IgD-CD27- double negative (DN) B cells have been observed, particularly in severe cases. This article aims to explore the significance of these extrafollicular B cell responses in the context of tissue inflammation and fibrosis, focusing on COVID-19 and IgG4-related disease (IgG4-RD).

Understanding Extrafollicular B Cell Responses

While previous studies have primarily focused on extrafollicular responses in the generation of autoantibodies, it is important to recognize that not all inflammatory diseases respond to B cell depletion, and autoantibodies may not be the central mediators in these cases.

Therefore, investigating extrafollicular B cell responses in the context of organ damage becomes crucial, as disease-specific B cell subsets may accumulate in tissues and contribute to inflammation and fibrosis beyond their role in antibody generation.

IgG4-Related Disease: An Example of B Cell-Mediated Fibrosis

IgG4-RD is a systemic autoimmune fibrotic disease that exhibits a remarkable response to B cell depletion, even leading to the reversal of tissue fibrosis. This indolent autoimmune disorder provides an opportunity to study the adaptive immune onset of fibrosis. Studies have shown that extrafollicular B cell activation is prominent in IgG4-RD, as the switching to IgG4 is driven by IL-4-expressing T helper cells (pre-GC T follicular helper cells) outside germinal centers. These findings suggest that extrafollicular B cell responses contribute to the pathology of IgG4-RD, emphasizing their potential role in driving inflammation and fibrosis.

COVID-19: Exploring Extrafollicular B Cell Infiltration

In COVID-19, lung fibrosis similar to that observed in previous coronavirus infections (SARS and MERS) has been observed on a larger scale. Fibrosis can range from persistent small lesions to severe lung impairment necessitating transplantation.

Macrophage activation by SARS-CoV-2 has been found to generate profibrotic macrophages, resembling those seen in idiopathic pulmonary fibrosis (IPF).

However, few studies have focused on infiltrating B lymphocyte subsets in severe COVID-19, and none have investigated draining lymph nodes simultaneously.

Comparing DN B Cell Subsets in COVID-19 and IgG4-RD

By comparing DN B cell subsets in blood and inflamed tissues of COVID-19 patients with those in IgG4-RD, researchers have identified disease-specific B cell populations. While both DN2 and DN3 B cells expand in the blood of COVID-19 and IgG4-RD patients, DN3 B cells dominate the population of disease-infiltrating B cells in COVID-19 lungs and fibrotic end-organs of IgG4-RD patients.

These DN3 B cells could potentially contribute to fibrosis initiation in both diseases, warranting further investigation into their role in persistent inflammation and fibrosis in post-acute COVID-19 sequelae.

Unraveling the Mechanisms and Implications

The effectiveness of B cell depletion in fibrotic diseases where autoantibodies do not play a central role raises intriguing questions. Understanding the biology of DN3 B cells and their potential to secrete pro-fibrotic molecules or collaborate with CD4+ T cells in driving fibrosis may lead to targeted therapies for IgG4-RD and other fibrotic diseases, including COVID-19. Moreover, DN2 and DN3 B cells have been associated with autoimmunity, suggesting their possible involvement in severe COVID-19 infections.

The Role of Immune Dysregulation

The generation of tissue-infiltrating extrafollicular DN3 B cells in both IgG4-RD and COVID-19 is associated with immune dysregulation. The massive inflammatory immune response triggered by SARS-CoV-2 likely contributes to the dysfunctional regulatory T cells observed in severe COVID-19, resulting in the breakdown of immunological tolerance and the generation of DN B cells. The exact ontogeny of DN B cell subsets is yet to be defined, but they likely arise following extrafollicular T-B collaboration.

Implications for COVID-19 and Beyond

Given the notable improvement in immune-mediated fibrotic diseases following anti-CD20-mediated B cell depletion, it is plausible to assume that activated B cell subsets during COVID-19 convalescence have the potential to drive fibrosis by secreting pro-fibrotic molecules or collaborating with CD4+ T cells.

Understanding the contribution of these B cells to fibrotic changes in the lungs and other tissues could shed light on the unwanted sequelae of COVID-19 infection. These fibrotic manifestations might result from T and B cell recognition of persistent SARS-CoV-2 antigens or the emergence of autoreactive T and B cells due to a breakdown in immunological tolerance.


The presence of disease-specific extrafollicular B cell populations, particularly DN3 B cells, in lymph nodes and inflamed tissues highlights their potential role as drivers of inflammation and fibrosis in both COVID-19 and IgG4-RD.

Investigating the biology and interactions of these B cell subsets could pave the way for targeted therapies in fibrotic diseases and provide insights into the pathogenesis of post-acute COVID-19 sequelae.

Further research is needed to unravel the intricate mechanisms underlying the contribution of extrafollicular B cells to tissue inflammation and fibrosis, ultimately leading to improved management strategies for these conditions.

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