Secondary Lymphoid Organ Alterations Underlying SARS-CoV-2 Humoral Response

Longitudinal studies of antibody-mediated immunity have revealed that humoral immunity is often short-lived and appears to lack durability (Brouwer et a.l. 2020; Long et al. 2020). Thus far, much of the understanding of the immune response to COVID-19 has largely focused on peripheral blood samples from COVID-patients with diverse disease severity. Kanoko et.al investigated the alterations in secondary lymphoid organs, where adaptive immune responses are generated, to better understand the mechanisms behind humoral immune response to SARS-CoV-2. Because COVID-19 most significantly affects the lungs, architecture and lymphocyte populations of thoracic lymph nodes from patients were imaged and quantitatively analyzed. Spleen and peripheral blood samples were also examined.

Germinal centers are important sites of selection of high-affinity B cells with long lifespans and pathogen-specific antibodies. Utilizing imaging approaches that preserve the architecture of human tissue, post-mortem lymph nodes were imaged from patients with severe disease who passed away within 8 days after admission and 15-36 days after admission (Figure 1A and 1B). In comparison to control lymph nodes from age-matched individuals, a dramatic loss of germinal centers and Bcl-6+ B cells was observed (Figure 1C and 1F). Bcl-6 is a critical transcription factor for T follicular helper cell differentiation and a key regulator of germinal centers. 

The authors also analyzed T follicular helper cell differentiation to better understand the possible mechanism behind germinal center loss. A striking loss of CD4+Bcl-6+ germinal center T follicular helper cells was found in spleen and lymph nodes (Figure 3B, 3D, 3F, and 3G). T follicular helper cells provide important signals in germinal centers for B cells to undergo clonal expansion and differentiate into memory B cells. The secondary lymphoid tissue was also examined for TNF-alpha expression, as germinal center loss in mouse models has been linked to  an abundance of TNF-alpha and can be reversed with TNF-alpha blockade (Ryg-Cornejo et al, 2016; Popescu et al, 2019). TNF-alpha was found to be abundantly expressed, compared to activated lymphoid tonsil tissue held as a control, both inside and outside of the follicle. The authors hypothesize that the elevated synthesis of TNF-alpha, possibly induced downstream of Th1 activation which was also present at elevated levels, blocks the differentiation of T follicular cells (Figure 4). 

Overall, the findings in this paper contribute to understanding the mechanisms of disease progression in patients with COVID-19. Germinal centers in secondary lymphoid organs provide crucial microenvironments for the development of potent antibody responses and memory B cells; thus, the loss of GC responses at acute stages of infection, may account for the variable and often short-lived antibody responses observed in COVID-19 patients. This also draws light as to why expectations of natural herd immunity may be elusive.