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Th17.1 lymphocytes: emerging players in the orchestra of immune-mediated inflammatory diseases

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Abstract

It is now well established that Th17 lymphocytes associate with myriad immune-mediated inflammatory diseases. Over the past one and a half decades, a subset of Th17 lymphocytes viz. Th17.1 lymphocytes has been identified in pre-clinical and clinical models of inflammatory rheumatic diseases. These lymphocytes secrete IL-17A (signature cytokine of Th17 lymphocytes) as well as IFN-γ (the signature cytokine of Th1 lymphocytes). They express the chemokine markers for Th1 (CXCR3) as well as Th17 (CCR6) lymphocytes. Th17.1 lymphocytes also express the drug efflux protein p-glycoprotein, which associates with resistance to corticosteroids and other immunosuppressive drugs. This narrative review overviews the evidence regarding Th17.1 lymphocytes in different inflammatory rheumatic diseases. It is now recognized that Th17.1 lymphocytes are increased in the synovial fluid of affected joints in rheumatoid arthritis (RA) and associate with poor treatment response to abatacept. Th17.1 lymphocytes from synovial fluid of RA are less responsive to immunosuppression than those from the peripheral blood. In sarcoidosis, Th17.1 lymphocytes are concentrated in mediastinal lymph nodes and alveolar lining. Such Th17.1 lymphocytes in sarcoidosis are the predominant source of IFN-γ in the sarcoid lung. Th17.1 lymphocytes are elevated in lupus and Takayasu arteritis and associate with disease activity. Future studies should evaluate isolated Th17.1 lymphocytes from peripheral blood or sites of pathology such as synovial fluid and assess their modulation with immunosuppressive therapy in vitro. The analysis of gene expression signature of isolated Th17.1 lymphocytes might enable the identification of newer therapeutic strategies specifically targeting these cell populations in inflammatory rheumatic diseases.

Key Points

• Th17.1 lymphocytes are a subset of Th17 lymphocytes secreting both IFN-γ and IL-17

• Th17.1 lymphocytes drive neutrophilic inflammation, granuloma formation, and corticosteroid resistance

• Th17.1 lymphocytes are elevated in rheumatoid arthritis and sarcoidosis at sites of inflammation

• Increased circulating Th17.1 lymphocytes have been identified in lupus and Takayasu arteritis and associate with active disease

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Data availability

Data pertaining to this narrative review shall be shared on reasonable request to the corresponding author (Durga Prasanna Misra, durgapmisra@gmail.com).

Abbreviations

αCD3:

Anti-CD3

αCD28:

Anti-CD28

AAV:

ANCA-associated vasculitis

ACPA:

Anti-citrullinated peptide antibody

ANCA:

Anti-neutrophil cytoplasmic antibody

anti-dsDNA:

Antibodies to double-stranded deoxy ribonucleic acid

BAL:

Bronchoalveolar lavage

DAS28-CRP:

Disease activity score assessed using 28 joint count and C-reactive protein

EGPA:

Eosinophilic granulomatosis with polyangiitis

FACS:

Fluorescence-associated cell sorting

GCA:

Giant cell arteritis

GM-CSF:

Granulocyte monocyte colony-stimulating factor

GPA:

Granulomatosis with polyangiitis

IFN-γ:

Interferon gamma

IL:

Interleukin

JIA:

Juvenile idiopathic arthritis

MACS:

Magnetic-associated cell sorting

MDR 1:

Multidrug resistance protein 1

mRNA:

Messenger ribonucleic acid

PD-1:

Programmed cell death 1

p-gp:

P-Glycoprotein

PMA:

Phorbol myristate acetate

PsA:

Psoriatic arthritis

RA:

Rheumatoid arthritis

scRNAseq:

Single-cell RNA sequencing

SLE:

Systemic lupus erythematosus

SLEDAI:

SLE disease activity index

SS:

Sjogren’s syndrome

TAK:

Takayasu arteritis

Tc:

T cytotoxic lymphocytes

TGF-β1:

Transforming growth factor beta 1

Th:

T helper lymphocytes

Treg:

Regulatory T lymphocytes

VitD3:

1,25 Di-hydroxy vitamin D3

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Acknowledgements

Durga Prasanna Misra acknowledges support from Indian Council of Medical Research (Grant No 5/4/1-2/2019-NCD-II) for his research on Takayasu arteritis.

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  1. Department of Clinical Immunology and Rheumatology, Sanjay Gandhi Postgraduate Institute of Medical Sciences (SGPGIMS), Lucknow-226014, India

    Durga Prasanna Misra & Vikas Agarwal

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Contributions

The conception and design of the study—DPM, VA; acquisition of data, analysis, and interpretation of data—DPM;

drafting the article—DPM; revising it critically for important intellectual content—VA; final approval of the version to be submitted—DPM, VA;

Agreement to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved—DPM, VA.

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Correspondence to Durga Prasanna Misra.

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Misra, D.P., Agarwal, V. Th17.1 lymphocytes: emerging players in the orchestra of immune-mediated inflammatory diseases. Clin Rheumatol 41, 2297–2308 (2022). https://doi.org/10.1007/s10067-022-06202-2

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