The role of CD6 in autoimmune diseases

Fox, David A.

doi:10.1038/s41423-018-0015-1

Cited by 3 publications

(2 citation statements)

References 23 publications

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“…Our results also suggest strong cell-cell interaction between Alcam + inflammatory macrophage expression and CD6 + recruited T-cells. Considering that the Alcam/CD6 co-stimulatory pathway has been implicated in collagen-induced arthritis and other models of autoimmunity (Fox, 2018; Li et al, 2020), and phase 1 clinical trials with anti-CD6 monoclonal antibody therapy in RA patients produced encouraging results (Rodriguez et al, 2017; Rodriguez et al, 2012), targeting this pathway to evaluate the effects on TNF-Tg arthritis and lymphatic pathology is warranted in future studies.…”

Section: Discussionmentioning

confidence: 99%

Multi-omics Analysis Identifies IgG2b Class-Switching with ALCAM-CD6 Co-Stimulation in Lymph Nodes During Advanced Inflammatory-Erosive Arthritis

Kenney

Rangel-Moreno

Yue

et al. 2022

Preprint

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Defective lymphatic drainage and B-cell translocation into joint-draining lymph node sinuses are pathogenic phenomena in patients with severe rheumatoid arthritis (RA). However, the molecular mechanisms underlying this lymphatic dysfunction remain poorly understood. Here, by utilizing spatial and single-cell transcriptomics in tumor necrosis factor transgenic (TNF-Tg) mice, we characterized functional genomic changes in popliteal lymph nodes (PLNs) of "Early" and "Advanced" RA to determine the mechanisms orchestrating B-cell differentiation. We first show that Ighg2b expression localized to Marco+ sinuses and negatively correlated with bone volumes in ipsilateral joints. We further reveal that Advanced PLNs exhibited a concomitant accumulation of iron-laden macrophages and T-cells. Mechanistically, crosstalk between ALCAM+ macrophages and CD6+ T-cells was identified as a co-stimulatory pathway promoting IgG2b class-switching. These findings were validated by immunohistochemistry, flow cytometry, ELISPOT, and clinical correlates. Collectively, we propose that ALCAM-CD6 co-stimulation activates T cells, initiating IgG2b class-switching and plasma cell differentiation in RA flare.

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Section: Discussionmentioning

confidence: 99%

Multi-omics Analysis Identifies IgG2b Class-Switching with ALCAM-CD6 Co-Stimulation in Lymph Nodes During Advanced Inflammatory-Erosive Arthritis

Kenney

Rangel-Moreno

Yue

et al. 2022

Preprint

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“…Inhibition studies of CD6 illustrate that this cellular marker regulates and influences leukocyte CD4 T cell extravasation across endothelial cell membranes and the blood brain barrier. CD6 is also preferentially expressed by activated monocytes, epithelial cells, and neurons [44,[107][108][109]. Other Morbilliviridae, such as MeV, utilize immune cell receptors like signaling lymphocyte activation molecules (SLAMF1/CD150) to replicate within the immune system and are expressed on T cells, B cells, natural killer (NK) cells, and DCs [110,111].…”

Section: Introductionmentioning

confidence: 99%

Immunopathogenesis of Nipah Virus Infection and Associated Immune Responses

Brown¹,

Gravier

Fricke³

et al. 2023

Immuno

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Pandemics in the last two centuries have been initiated by causal pathogens that include Severe Acute Coronavirus 2 (SARS-CoV-2) and Influenza (e.g., the H1N1 pandemic of 2009). The latter is considered to have initiated two prior pandemics in 1918 and 1977, known as the “Spanish Flu” and “Russian Flu”, respectively. Here, we discuss other emerging infections that could be potential public health threats. These include Henipaviruses, which are members of the family Paramyxoviridae that infect bats and other mammals. Paramyxoviridae also include Parainfluenza and Mumps viruses (Rubulavirus) but also Respiratory Syncytial virus (RSV) (Pneumovirus). Additionally included is the Measles virus, recorded for the first time in writing in 1657 (Morbillivirus). In humans and animals, these may cause encephalitis or respiratory diseases. Recently, two more highly pathogenic class 4 viral pathogens emerged. These were named Hendra Henipavirus (HeV) and Nipah Henipavirus (NiV). Nipah virus is a negative-sense single-stranded ribonucleic acid ((−) ssRNA) virus within the family Paramyxoviridae. There are currently no known therapeutics or treatment regimens licensed as effective in humans, with development ongoing. Nipah virus is a lethal emerging zoonotic disease that has been neglected since its characterization in 1999 until recently. Nipah virus infection occurs predominantly in isolated regions of Malaysia, Bangladesh, and India in small outbreaks. Factors that affect animal–human disease transmission include viral mutation, direct contact, amplifying reservoirs, food, close contact, and host cell mutations. There are different strains of Nipah virus, and small outbreaks in humans limit known research and surveillance on this pathogen. The small size of outbreaks in rural areas is suggestive of low transmission. Person-to-person transmission may occur. The role that zoonotic (animal–human) or host immune system cellular factors perform therefore requires analysis. Mortality estimates for NiV infection range from 38–100% (averaging 58.2% in early 2019). It is therefore critical to outline treatments and prevention for NiV disease in future research. The final stages of the disease severely affect key organ systems, particularly the central nervous system and brain. Therefore, here we clarify the pathogenesis, biochemical mechanisms, and all research in context with known immune cell proteins and genetic factors.

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Multi-omics analysis identifies IgG2b class-switching with ALCAM-CD6 co-stimulation in joint-draining lymph nodes during advanced inflammatory-erosive arthritis

Kenney,

Rangel-Moreno,

Peng

et al. 2023

Front. Immunol.

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IntroductionDefective lymphatic drainage and translocation of B-cells in inflamed (Bin) joint-draining lymph node sinuses are pathogenic phenomena in patients with severe rheumatoid arthritis (RA). However, the molecular mechanisms underlying this lymphatic dysfunction remain poorly understood. Herein, we utilized multi-omic spatial and single-cell transcriptomics to evaluate altered cellular composition (including lymphatic endothelial cells, macrophages, B-cells, and T-cells) in the joint-draining lymph node sinuses and their associated phenotypic changes and cell-cell interactions during RA development using the tumor necrosis factor transgenic (TNF-Tg) mouse model.MethodsPopliteal lymph nodes (PLNs) from wild-type (n=10) and TNF-Tg male mice with “Early” (5 to 6-months of age; n=6) and “Advanced” (>8-months of age; n=12) arthritis were harvested and processed for spatial transcriptomics. Single-cell RNA sequencing (scRNAseq) was performed in PLNs from the TNF-Tg cohorts (n=6 PLNs pooled/cohort). PLN histopathology and ELISPOT along with ankle histology and micro-CT were evaluated. Histopathology of human lymph nodes and synovia was performed for clinical correlation.ResultsAdvanced PLN sinuses exhibited an increased Ighg2b/Ighm expression ratio (Early 0.5 ± 0.1 vs Advanced 1.4 ± 0.5 counts/counts; p<0.001) that significantly correlated with reduced talus bone volumes in the afferent ankle (R2 = 0.54, p<0.001). Integration of single-cell and spatial transcriptomics revealed the increased IgG2b+ plasma cells localized in MARCO+ peri-follicular medullary sinuses. A concomitant decreased Fth1 expression (Early 2.5 ± 0.74 vs Advanced 1.0 ± 0.50 counts, p<0.001) within Advanced PLN sinuses was associated with accumulation of iron-laden Prussian blue positive macrophages in lymph nodes and synovium of Advanced TNF-Tg mice, and further validated in RA clinical samples. T-cells were increased 8-fold in Advanced PLNs, and bioinformatic pathway assessment identified the interaction between ALCAM+ macrophages and CD6+ T-cells as a plausible co-stimulatory mechanism to promote IgG2b class-switching.DiscussionCollectively, these data support a model of flare in chronic TNF-induced arthritis in which loss of lymphatic flow through affected joint-draining lymph nodes facilitates the interaction between effluxing macrophages and T-cells via ALCAM-CD6 co-stimulation, initiating IgG2b class-switching and plasma cell differentiation of the expanded Bin population. Future work is warranted to investigate immunoglobulin clonality and potential autoimmune consequences, as well as the efficacy of anti-CD6 therapy to prevent these pathogenic events.

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The role of CD6 in autoimmune diseases

Cited by 3 publications

References 23 publications

Multi-omics Analysis Identifies IgG2b Class-Switching with ALCAM-CD6 Co-Stimulation in Lymph Nodes During Advanced Inflammatory-Erosive Arthritis

Multi-omics Analysis Identifies IgG2b Class-Switching with ALCAM-CD6 Co-Stimulation in Lymph Nodes During Advanced Inflammatory-Erosive Arthritis

Immunopathogenesis of Nipah Virus Infection and Associated Immune Responses

Multi-omics analysis identifies IgG2b class-switching with ALCAM-CD6 co-stimulation in joint-draining lymph nodes during advanced inflammatory-erosive arthritis

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