Biomarkers in autoimmune diseases of the central nervous system

One hallmark of some autoimmune diseases is the individual variability of symptoms. Organs affected by the disease differ between patients, making diagnosis of affected organs a challenge. Although numerous studies have investigated the correlation between T cell antigen receptor (TCR) repertoires and development of infectious and immune diseases, the correlation between TCR repertoires and variations in disease symptoms among individuals remains unclear. This study investigated correlation of TCR repertoires in blood T cells with severity of an autoimmune phenotype that varies among individuals. We sequenced TCR repertoires in the blood and stomachs of mice deficient in autoimmune regulator (Aire) (AIRE KO), a mouse model of human autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED). Data analysis revealed that degree of similarity in TCR repertoires between the blood and stomach differs among individual AIRE KO mice and reflects the severity of stomach inflammation. This suggests the existence of blood TCR repertoires that can be used to predict affected organs. Indeed, we identified a set of TCR sequences whose frequencies in blood correlated with severity of stomach manifestations. Our results highlight the potential of using TCR repertoires not just for diagnosis of disease development, but also for diagnosis of affected organs in autoimmune diseases.

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Section: Introductionmentioning

confidence: 99%

TCR Repertoire Analysis of CD4-Positive T Cells from Blood and an Affected Organ in an Autoimmune Mouse Model

Ishikawa

Horie

Takakura

et al. 2023

Preprint

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“…Because of the heterogeneous nature of autoimmune diseases, diagnosis of affected organs is necessary. In addition to the approach by detecting organ-specific protein markers (Suzuki et al, 2008;Zhang et al, 2023) (e.g., Neurofilament light chain in multiple sclerosis), it would be desirable to be able to use TCR repertoire analysis for diagnosis. TCR repertoire is formed by a combination of the hypervariable complementaritydetermining region 3 (CDR3) loop of TCRs on their cell membranes and diverse V(D)J recombination in the thymus, allowing T cells to recognize myriad antigens in the body (Schatz & Ji, 2011).…”

mentioning

confidence: 99%

T‐cell receptor repertoire analysis of CD4‐positive T cells from blood and an affected organ in an autoimmune mouse model

Ishikawa,

Horie,

Takakura

et al. 2023

Genes to Cells

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One hallmark of some autoimmune diseases is the variability of symptoms among individuals. Organs affected by the disease differ between patients, posing a challenge in diagnosing the affected organs. Although numerous studies have investigated the correlation between T cell antigen receptor (TCR) repertoires and the development of infectious and immune diseases, the correlation between TCR repertoires and variations in disease symptoms among individuals remains unclear. This study aimed to investigate the correlation of TCRα and β repertoires in blood T cells with the extent of autoimmune signs that varies among individuals. We sequenced TCRα and β of CD4+CD44highCD62Llow T cells in the blood and stomachs of mice deficient in autoimmune regulator (Aire) (AIRE KO), a mouse model of human autoimmune polyendocrinopathy‐candidiasis‐ectodermal dystrophy. Data analysis revealed that the degree of similarity in TCR sequences between the blood and stomach varied among individual AIRE KO mice and reflected the extent of T cell infiltration in the stomach. We identified a set of TCR sequences whose frequencies in blood might correlate with extent of the stomach manifestations. Our results propose a potential of using TCR repertoires not only for diagnosing disease development but also for diagnosing affected organs in autoimmune diseases.

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The murine meninges acquire lymphoid tissue properties and harbour autoreactive B cells during chronicTrypanosoma bruceiinfection

Quintana

Sinton

Chandrasegaran

et al. 2023

Preprint

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The meningeal space is an important structure in the brain borders, which provides immunosurveillance for the central nervous system, but the impact of infections on the meningeal immune landscape is far from being fully understood. The extracellular protozoan parasite Trypanosoma brucei, which causes Human African Trypanosomiasis (HAT) or sleeping sickness, accumulate in the meningeal spaces, ultimately inducing severe meningitis and resulting in death if left untreated. Thus, sleeping sickness represents an attractive model to study immunological dynamics in the meninges during infection. Here, combining single cell transcriptomics and mass cytometry by time of flight (CyTOF), coupled with in vivo interventions, we found that chronic T. brucei infection triggers the development of ectopic lymphoid aggregates (ELAs) in the murine meninges during chronic infection. These infection-induced ectopic structures are defined by the presence of ER-TR7+ fibroblastic reticular cells (FRCs) and follicular dendritic cells (FDCs) that initiate a signalling cascade driving local T cell activation towards a T follicular helper (TFH)-like phenotype, as well as B cell class switching. Furthermore, the GC-like B cells found in the infected meninges produce high-affinity autoantibodies able to recognise mouse brain antigens. We found that systemic lymphotoxin β (LTβ) signalling blockade led to a significant depletion of meningeal FDC-like cells and autoreactive B cells, indicating that LTβ signalling is critical to induce and maintain local responses in the meninges. In humans, we identified the presence of autoreactive IgG antibodies able to recognise human brain lysates in the cerebrospinal fluid of second stage HAT patients compared to first stage HAT patients, consistent with our findings in experimental infections. Taken together, our data provide evidence that the meningeal immune response results in the acquisition of lymphoid tissue-like properties during chronic T. brucei infection, broadening our understanding of meningeal immunity in the context of chronic infections. These findings have wider implications for understanding the mechanisms underlying the formation ELAs during chronic inflammation resulting in autoimmunity in mice and humans, as observed in other autoimmune neurodegenerative disorders such as neuropsychiatric lupus and multiple sclerosis.

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Biomarkers in autoimmune diseases of the central nervous system

Cited by 5 publications

References 108 publications

TCR Repertoire Analysis of CD4-Positive T Cells from Blood and an Affected Organ in an Autoimmune Mouse Model

TCR Repertoire Analysis of CD4-Positive T Cells from Blood and an Affected Organ in an Autoimmune Mouse Model

T‐cell receptor repertoire analysis of CD4‐positive T cells from blood and an affected organ in an autoimmune mouse model

The murine meninges acquire lymphoid tissue properties and harbour autoreactive B cells during chronicTrypanosoma bruceiinfection

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