Expansion of circulating T cells resembling follicular helper T cells is a fixed phenotype that identifies a subset of severe systemic lupus erythematosus

Abstract

Objective. In the sanroque mouse model of lupus, pathologic germinal centers (GCs) arise due to increased numbers of follicular helper T (Tfh) cells, resulting in high-affinity anti-double-stranded DNA antibodies that cause end-organ inflammation, such as glomerulonephritis. The purpose of this study was to examine the hypothesis that this pathway could account for a subset of patients with systemic lupus erythematosus (SLE).Methods. An expansion of Tfh cells is a causal, and therefore consistent, component of the sanroque mouse phenotype. We validated the enumeration of circulating T cells resembling Tfh cells as a biomarker of this expansion in sanroque mice, and we performed a comprehensive comparison of the surface phenotype of circulating and tonsillar Tfh cells in humans. This circulating biomarker was enumerated in SLE patients (n ‫؍‬ 46), Sjögren's syndrome patients (n ‫؍‬ 17), and healthy controls (n ‫؍‬ 48) and was correlated with disease activity and end-organ involvement.Results. In sanroque mice, circulating Tfh cells increased in proportion to their GC counterparts, making circulating Tfh cells a feasible human biomarker of this novel mechanism of breakdown in GC tolerance. In a subset of SLE patients (14 of 46), but in none of the controls, the levels of circulating Tfh cells (defined as circulating CXCR5؉CD4؉ cells with high expression of Tfh-associated molecules, such as inducible T cell costimulator or programmed death 1) were increased. This cellular phenotype did not vary with time, disease activity, or treatment, but it did correlate with the diversity and titers of autoantibodies and with the severity of end-organ involvement.Conclusion. These findings in SLE patients are consistent with the autoimmune mechanism in sanroque mice and identify Tfh effector molecules as possible therapeutic targets in a recognizable subset of patients with SLE.

Immunologic characteristics of HIV‐infected individuals who make broadly neutralizing antibodies

“…in sanroque mice homozygous for a loss of function mutation in Roquin, which results in high ICOS expression on Tfh cells and excessive Tfh cell accumulation, there is spontaneous B‐cell activation, GC formation, and autoantibody production, and the animals develop a lupus‐like phenotype 212, 213. Likewise increased numbers of circulating CXCR5 +  CD4 + T cells, frequencies of which correlate with autoantibody titers, are observed in patients with SLE and other autoimmune diseases including Sjogren's syndrome and myasthenia gravis 162, 214…”

The darker side of follicular helper T cells: from autoimmunity to immunodeficiency

“…50 Recent studies have further provided clearer evidence on the role of T FH cells in promotion of both systemic and organ-specific autoimmune diseases in humans. [51][52][53][54][55] Simpson et al 51 performed an elegant study investigating the role of T FH cells in patients with SLE and Sjogren's syndrome. They found an overrepresented population of CD4 1 CXCR5 1 T FH cell-like cells in the blood, referred to as circulating T FH (T FHC ) cells, of a subset of the SLE patients (14 out of 46), which expressed ICOS and PD-1 compared with healthy controls.…”

“…However, it should be noted that although T FHC cells resemble T FH cells in terms of ICOS and PD-1 expression, T FHC cells in SLE patients do not express Bcl6 and IL-21 that are hallmarks of classic T FH cells. 51 This discrepancy poses a pertinent question as to whether T FHC and T FH cells are indeed related. It may be that T FHC cells are a subset of T FH cells residing in the lymphoid organs that may downregulate Bcl6 while migrating to the systemic circulation as T FHC cells.…”

“…The patients deficient in ICOS and CD40L lack T FHC cells, whereas T FHC cells expressing ICOS are overrepresented in SLE and rheumatoid arthritis patients. 10,51,53 T FH CELLS AND IMMUNODEFICIENCY Immunodeficiency is a pathological condition where the immune response is compromised or absent. Defects in humoural immune response lead to the humoral immunodeficiencies, such as common variable immunodeficiency (CVID), X-linked hyper IgM syndrome (HIGM) and X-linked lymphoproliferative disease (XLP).…”

Follicular helper T cells in immune homeostasis

“…Interestingly, cT FH cells, which are identified in a study involving systemic lupus erythematosus patients, express CXCR5, ICOS and PD-1, but not BCL6 and IL-21. 7 Given that BCL6 and IL-21 are the most critical transcription factor and cytokine for T FH …”