Th17 pathogenic

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Th17 pathogenic refers to a distinct phenotype of Th17 cells which is associated with immunopathology. The development of the pathogenic phenotype can be shaped by various environmental stimuli and genetic factors. [1] [2] In humans, Th17 pathogenic cells are associated with diseases like multiple sclerosis (MS) [3] or rheumatoid arthritis (RA) [4] and in mice with experimental autoimmune encephalomyelitis (EAE). [5] Th17 pathogenic cells are known to display pro-inflammatory features like expressing transcription factor T-bet and secreting cytokine IFNγ, resembling Th1-like phenotype. Th17 cells are a very heterogenous subset and can switch to display all T helper-like phenotype markers including those typical for Th2, Treg and Tfh. [2] [4]

Contents

Th17 cells gain the pathogenic phenotype by induction with pro-inflammatory cytokines IL-1β, IL-6 and IL-23 during their maturation. On the other hand, regulation of the Th17 immune response by TGFβ1 and IL-10 is known to inhibit Th17 pathogenicity. GM-CSF and IL-17 were recognised as the main effector cytokines secreted by Th17 pathogenic cells that promote the development of immunopathology. [2] [6]

Key molecules in Th17 pathogenic development

Foxo1

An important molecule in the Th17 pathogenic phenotype generation is the transcription factor Foxo1. Foxo1 inhibits hallmark Th17 transcription factor RORγt from enhancing the expression of the IL-1 and IL-23 receptors. Therefore, the Foxo1 deficient function results in over-expression of IL-1R and IL-23R which are one of the drivers of the Th17 pathogenic development. This inhibition of Foxo1 could be done through multiple mechanisms including miRNA regulation or activation of SGK1 kinase, which reacts to higher levels of NaCl in the body. [1] [2] [7] It is suggested that high consumption of a salty diet can lead to the development of Th17 pathogenic cells. [7]

RBPJ

RBPJ transcriptional regulator involved in the Notch signalling pathway promotes Th17 pathogenicity by activating the expression of IL23R and repressing the expression of IL-10. The following higher responsiveness to IL-23 stimulation, which is one of the key cytokines involved in Th17 pathogenic switch, and reduced production of regulatory anti-inflammatory IL-10 result in the phenotype change. Mice with RBPJ deficiency have less severe manifestations and faster recovery from experimental autoimmune encephalomyelitis due to fewer Th17 cells developing the pathogenic phenotype. [5]

CD5L

CD5L protein is a lipid metabolism regulator. In Th17 cells CD5L is predominantly expressed in non-pathogenic ones, where it functions as a pathogenicity repressor. Loss of CD5L expression drives Th17 cells to the pathogenic phenotype through the subsequent changes in lipid metabolism, and through the alteration of binding of the transcription factor RORγt to its target genes. More specifically, the CD5L deficit in Th17 cells switches the fatty acid balance in favour of saturated fatty acids (SFA) and limits cholesterol synthesis, RORγt is regulated by polyunsaturated fatty acid (PUFA) derived ligands whose availability in CD5L deficient cells is limited. CD5L expression can be lost in response to IL23R signalling. [8]

Th17 pathogenic in disease

Rheumatoid arthritis

Th17 pathogenic cells were identified as one of the cross-reactive cell subsets causing inflammatory synovial and cartilage disruption in joints causing rheumatoid arthritis disease. Th17 pathogenic cells express CCR6 chemokine molecule which after binding to its ligand promotes the migration to the joints and synovial tissue. The non-immune cells of synovial tissue are expressing the CCR6 ligands upon pro-inflammatory stimulation with IL-17, IL-1β, GM-CSF cytokines secreted by originally recruited immune cells, this is one of the mechanisms of the vicious circle of chronic joint inflammation in rheumatoid arthritis. [4]

Multiple sclerosis

Th17 pathogenic cells were identified as one of the cross-reactive cell subsets disrupting the protective myelin sheath of neurons causing multiple sclerosis disease. Elevated levels of IL-17, IL-23, GM-CSF pro-inflammatory cytokines associated with Th17 pathogenic cells play a key role in demyelination and consequent multiple sclerosis manifestations. The migration of Th17 pathogenic cells to the CNS is critical in multiple sclerosis progression and it is mediated by CCR6 chemokine expressed on Th17 pathogenic cell surface. [3] [2]

Obesity

Microbiota dysbiosis, disruption of metabolic functions and homeostasis with subsequent high levels of saturated fatty acids (SFA) and cholesterol present in the gastrointestinal tract of obese patients are leading to chronic low-grade inflammation which has an impact on Th17 pathogenic formation. ACC1 in Th17 cells is over-activated in response to a high-fat diet. ACC1 regulates the development of pathogenic phenotype by altering the fatty acid metabolism and the availability of lipid-derived regulatory partners of transcription factors including RORγt. [9] The function of important molecules in Th17 pathogenic development like IL-23, CD5L, ACC1 and others are altered in patients with obesity contributing to the phenotype switch. [6] [8] [9]

Other diseases associated with the involvement of Th17 pathogenic cells are psoriasis, diabetes, systemic lupus erythematosus and others. [2] [6]

Related Research Articles

<span class="mw-page-title-main">Rheumatoid arthritis</span> Type of autoimmune arthritis

Rheumatoid arthritis (RA) is a long-term autoimmune disorder that primarily affects joints. It typically results in warm, swollen, and painful joints. Pain and stiffness often worsen following rest. Most commonly, the wrist and hands are involved, with the same joints typically involved on both sides of the body. The disease may also affect other parts of the body, including skin, eyes, lungs, heart, nerves and blood. This may result in a low red blood cell count, inflammation around the lungs, and inflammation around the heart. Fever and low energy may also be present. Often, symptoms come on gradually over weeks to months.

<span class="mw-page-title-main">Cytotoxic T cell</span> T cell that kills infected, damaged or cancerous cells

A cytotoxic T cell (also known as TC, cytotoxic T lymphocyte, CTL, T-killer cell, cytolytic T cell, CD8+ T-cell or killer T cell) is a T lymphocyte (a type of white blood cell) that kills cancer cells, cells that are infected by intracellular pathogens (such as viruses or bacteria), or cells that are damaged in other ways.

<span class="mw-page-title-main">Interleukin 26</span>

Interleukin-26 (IL-26) is a protein that in humans is encoded by the IL26 gene.

<span class="mw-page-title-main">Interleukin 20</span>

Interleukin 20 (IL20) is a protein that is in humans encoded by the IL20 gene which is located in close proximity to the IL-10 gene on the 1q32 chromosome. IL-20 is a part of an IL-20 subfamily which is a part of a larger IL-10 family.

<span class="mw-page-title-main">Interleukin 19</span>

Interleukin 19 (IL-19) is an immunosuppressive protein that belongs to the IL-10 cytokine subfamily.

<span class="mw-page-title-main">STAT4</span> Protein-coding gene in the species Homo sapiens

Signal transducer and activator of transcription 4 (STAT4) is a transcription factor belonging to the STAT protein family, composed of STAT1, STAT2, STAT3, STAT5A, STAT5B, STAT6. STAT proteins are key activators of gene transcription which bind to DNA in response to cytokine gradient. STAT proteins are a common part of Janus kinase (JAK)- signalling pathways, activated by cytokines.STAT4 is required for the development of Th1 cells from naive CD4+ T cells and IFN-γ production in response to IL-12. There are two known STAT4 transcripts, STAT4α and STAT4β, differing in the levels of interferon-gamma production downstream.

Osteoimmunology is a field that emerged about 40 years ago that studies the interface between the skeletal system and the immune system, comprising the “osteo-immune system”. Osteoimmunology also studies the shared components and mechanisms between the two systems in vertebrates, including ligands, receptors, signaling molecules and transcription factors. Over the past decade, osteoimmunology has been investigated clinically for the treatment of bone metastases, rheumatoid arthritis (RA), osteoporosis, osteopetrosis, and periodontitis. Studies in osteoimmunology reveal relationships between molecular communication among blood cells and structural pathologies in the body.

T helper 17 cells (Th17) are a subset of pro-inflammatory T helper cells defined by their production of interleukin 17 (IL-17). They are related to T regulatory cells and the signals that cause Th17s to differentiate actually inhibit Treg differentiation. However, Th17s are developmentally distinct from Th1 and Th2 lineages. Th17 cells play an important role in maintaining mucosal barriers and contributing to pathogen clearance at mucosal surfaces; such protective and non-pathogenic Th17 cells have been termed as Treg17 cells.

<span class="mw-page-title-main">RAR-related orphan receptor gamma</span> Cellular receptor

RAR-related orphan receptor gamma (RORγ) is a protein that in humans is encoded by the RORC gene. RORγ is a member of the nuclear receptor family of transcription factors. It is mainly expressed in immune cells and it also regulates circadian rhythms. It may be involved in the progression of certain types of cancer.

<span class="mw-page-title-main">TBX21</span> Protein-coding gene in the species Homo sapiens

T-box transcription factor TBX21, also called T-bet is a protein that in humans is encoded by the TBX21 gene. Though being for long thought of only as a master regulator of type 1 immune response, T-bet has recently been shown to be implicated in development of various immune cell subsets and maintenance of mucosal homeostasis.

Interleukin 35 (IL-35) is a recently discovered anti-inflammatory cytokine from the IL-12 family. Member of IL-12 family - IL-35 is produced by wide range of regulatory lymphocytes and plays a role in immune suppression. IL-35 can block the development of Th1 and Th17 cells by limiting early T cell proliferation.

<span class="mw-page-title-main">IL17A</span> Protein-coding gene in the species Homo sapiens

Interleukin-17A is a protein that in humans is encoded by the IL17A gene. In rodents, IL-17A used to be referred to as CTLA8, after the similarity with a viral gene.

<span class="mw-page-title-main">Autoimmune disease</span> Abnormal immune response to a normal body part

An autoimmune disease is a condition arising from an abnormal immune response to a functioning body part. At least 80 types of autoimmune diseases have been identified, with some evidence suggesting that there may be more than 100 types. Nearly any body part can be involved. Common symptoms can be diverse and transient, ranging from mild to severe, and generally include low grade fever and feeling tired.

T helper 3 cells (Th3) are a subset of T lymphocytes with immunoregulary and immunosuppressive functions, that can be induced by administration of foreign oral antigen. Th3 cells act mainly through the secretion of anti-inflammatory cytokine transforming growth factor beta (TGF-β). Th3 have been described both in mice and human as CD4+FOXP3− regulatory T cells. Th3 cells were first described in research focusing on oral tolerance in the experimental autoimmune encephalitis (EAE) mouse model and later described as CD4+CD25−FOXP3−LAP+ cells, that can be induced in the gut by oral antigen through T cell receptor (TCR) signalling.

Mucosal associated invariant T cells make up a subset of T cells in the immune system that display innate, effector-like qualities. In humans, MAIT cells are found in the blood, liver, lungs, and mucosa, defending against microbial activity and infection. The MHC class I-like protein, MR1, is responsible for presenting bacterially-produced vitamin B2 and B9 metabolites to MAIT cells. After the presentation of foreign antigen by MR1, MAIT cells secrete pro-inflammatory cytokines and are capable of lysing bacterially-infected cells. MAIT cells can also be activated through MR1-independent signaling. In addition to possessing innate-like functions, this T cell subset supports the adaptive immune response and has a memory-like phenotype. Furthermore, MAIT cells are thought to play a role in autoimmune diseases, such as multiple sclerosis, arthritis and inflammatory bowel disease, although definitive evidence is yet to be published.

Innate lymphoid cells (ILCs) are the most recently discovered family of innate immune cells, derived from common lymphoid progenitors (CLPs). In response to pathogenic tissue damage, ILCs contribute to immunity via the secretion of signalling molecules, and the regulation of both innate and adaptive immune cells. ILCs are primarily tissue resident cells, found in both lymphoid, and non- lymphoid tissues, and rarely in the blood. They are particularly abundant at mucosal surfaces, playing a key role in mucosal immunity and homeostasis. Characteristics allowing their differentiation from other immune cells include the regular lymphoid morphology, absence of rearranged antigen receptors found on T cells and B cells, and phenotypic markers usually present on myeloid or dendritic cells.

Regulatory B cells (Bregs or Breg cells) represent a small population of B cells that participates in immunomodulation and in the suppression of immune responses. The population of Bregs can be further separated into different human or murine subsets such as B10 cells, marginal zone B cells, Br1 cells, GrB+B cells, CD9+ B cells, and even some plasmablasts or plasma cells. Bregs regulate the immune system by different mechanisms. One of the main mechanisms is the production of anti-inflammatory cytokines such as interleukin 10 (IL-10), IL-35, or transforming growth factor beta (TGF-β). Another known mechanism is the production of cytotoxic Granzyme B. Bregs also express various inhibitory surface markers such as programmed death-ligand 1 (PD-L1), CD39, CD73, and aryl hydrocarbon receptor. The regulatory effects of Bregs were described in various models of inflammation, autoimmune diseases, transplantation reactions, and in anti-tumor immunity.

<span class="mw-page-title-main">Type 3 innate lymphoid cells</span>

Type 3 innate lymphoid cells (ILC3) are immune cells from the lymphoid lineage that are part of the innate immune system. These cells participate in innate mechanisms on mucous membranes, contributing to tissue homeostasis, host-commensal mutualism and pathogen clearance. They are part of a heterogeneous group of innate lymphoid cells, which is traditionally divided into three subsets based on their expression of master transcription factors as well as secreted effector cytokines - ILC1, ILC2 and ILC3.

Epigenetics of autoimmune disorders is the role that epigenetics play in autoimmune diseases. Autoimmune disorders are a diverse class of diseases that share a common origin. These diseases originate when the immune system becomes dysregulated and mistakenly attacks healthy tissue rather than foreign invaders. These diseases are classified as either local or systemic based upon whether they affect a single body system or if they cause systemic damage.

Fionula Brennan was an immunologist and Professor of Cytokine Immunopathology at the Kennedy Institute of Rheumatology.

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