Effects of <scp>CXCL</scp>13 inhibition on lymphoid follicles in models of autoimmune disease

Finch, Donna K.; Ettinger, Rachel; Karnell, Jodi L.; Herbst, Ronald; Sleeman, Matthew A.

doi:10.1111/eci.12063

Cited by 70 publications

(60 citation statements)

References 72 publications

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“…Plasma CXCL13 has been proposed to serve as a biomarker of autoimmune diseases, such as rheumatoid arthritis, systemic lupus erythematosus, Sjogren's syndrome, and Myasthenia Gravis (41). Elevated plasma CXCL13 was detected in patients with systemic lupus erythematosus and further increased in individuals with severe disease presenting with nephritis or anti-DNA Ab responses (19).…”

Section: Discussionmentioning

confidence: 99%

CXCL13 is a plasma biomarker of germinal center activity

Havenar-Daughton

Lindqvist

Heit

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

301

311

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Significantly higher levels of plasma CXCL13 [chemokine (C-X-C motif) ligand 13] were associated with the generation of broadly neutralizing antibodies (bnAbs) against HIV in a large longitudinal cohort of HIV-infected individuals. Germinal centers (GCs) perform the remarkable task of optimizing B-cell Ab responses. GCs are required for almost all B-cell receptor affinity maturation and will be a critical parameter to monitor if HIV bnAbs are to be induced by vaccination. However, lymphoid tissue is rarely available from immunized humans, making the monitoring of GC activity by direct assessment of GC B cells and germinal center CD4 + T follicular helper (GC Tfh) cells problematic. The CXCL13-CXCR5 [chemokine (C-X-C motif) receptor 5] chemokine axis plays a central role in organizing both B-cell follicles and GCs. Because GC Tfh cells can produce CXCL13, we explored the potential use of CXCL13 as a blood biomarker to indicate GC activity. In a series of studies, we found that plasma CXCL13 levels correlated with GC activity in draining lymph nodes of immunized mice, immunized macaques, and HIV-infected humans. Furthermore, plasma CXCL13 levels in immunized humans correlated with the magnitude of Ab responses and the frequency of ICOS + (inducible T-cell costimulator) Tfh-like cells in blood. Together, these findings support the potential use of CXCL13 as a plasma biomarker of GC activity in human vaccine trials and other clinical settings.T he germinal center (GC) reaction is a critical immunological process that occurs in draining lymph nodes after immunization (1). The GC response consists of antigen-specific B cells undergoing affinity maturation through a process of somatic hypermutation (SHM) of the B-cell receptor. SHM is necessary for producing high-affinity Ab responses after immunizations and infections. Influenza neutralizing Abs have substantial SHM. Particularly high levels of SHM, 15-30% amino acid mutation (2, 3), are present and necessary for broad Ab neutralization of diverse HIV strains (4, 5). Therefore, as candidate influenza and HIV vaccines are evaluated for the ability to induce broadly neutralizing antibodies (bnAbs), the quantitation and functional characterization of GC responses will be a key parameter for study. Serological analysis of vaccine-specific Ab titers provides important information, but those data are limited. Serological outcomes are measured at time points long after initial immunizations. Neutralizing Ab responses are commonly only measurable after multiple boosts. Those outcomes likely depend on GC activity and affinity maturation at much earlier time points. Several state of the art HIV vaccine strategies rely on long, multistage immunization protocols (6, 7). With bnAb responses as the goal, means of early analysis of the immune response will be essential to understand and improve on vaccination schemes that may end in failure or only partial success. One critical parameter to assess will be the ability of each immunization to generate GC responses.Central to the GC re...

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Section: Discussionmentioning

confidence: 99%

CXCL13 is a plasma biomarker of germinal center activity

Havenar-Daughton

Lindqvist

Heit

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

301

311

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“…In pSS animal models spontaneous development of splenic GCs precedes the lymphocytic infiltration of the salivary gland suggesting that tertiary lymphoid structures may arise from trafficking of activated T and B cells to sites of inflammation [10]. Interestingly, blockade of CXCL13 was sufficient to disrupt follicular architecture of the spleen but did not impact tertiary lymphoid structures in the salivary gland [11]. A recent study also implicated EBV dysregulation in the formation of ectopic lymphoid structures in pSS with evidence of EBV infection in B cells and plasma cells in the salivary gland of pSS patients with ectopic structures.…”

Section: Target Tissue Effectsmentioning

confidence: 99%

New insights into B cell biology in systemic lupus erythematosus and Sjögren's syndrome

Bird

Meednu

Anolik

2015

Current Opinion in Rheumatology

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Purpose of review Our understanding of the physiological and pathogenic functions of B cells in systemic lupus erythematosus (SLE) and Sjogren’s syndrome (pSS) continues to expand. In this review, we discuss novel insights published in the last 18 months into the roles of B cells in systemic autoimmunity. Recent findings Data has continued to expand the diverse mechanisms by which innate immune signals including toll like receptors (TLR) may regulate the B cell compartment. Localized B cells and long-lived plasma cells have been identified as playing an important role in target tissue including the development of ectopic lymphoid structures in kidney and salivary gland. In addition to pathogenic roles for B cells, there is mounting evidence for regulatory B cell subsets that play a protective role and new insights into the signals that regulate their development. Summary The past few years have provided insights into the multiple paths by which innate immune signals can lead to B cell activation in SLE and pSS and the increasingly diverse ways in which B cells contribute to disease expression. Further understanding the imbalance between protective and pathogenic functions for B cells in disease including in understudied target tissue should yield new treatment approaches.

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“…3 A key phenomenon in the pathogenesis of autoimmune diseases is the formation of ectopic lymphoid aggregates with germinal center-like structures in the inflamed tissues, which contain proliferating B lymphocytes, plasma cells, follicular helper CD4 þ T lymphocytes, and a network of follicular dendritic cells. [4][5][6] The formation and maintenance of ectopic lymphoid structures is dependent on the expression of lymphoid chemokines, such as stromal cell-derived factor-1/CXCL12, and B cell attracting chemokine-1/CXCL13 and their specific receptors CXCR4 and CXCR5, respectively. [4][5][6] Within the chemokine family, scavenger receptor for phosphatidyl serine and oxidized low-density lipoprotein/CXCL16 and fractalkine/CX3CL1 are exceptional in that they can be found in both membrane-bound and soluble forms.…”

mentioning

confidence: 99%

“…[4][5][6] The formation and maintenance of ectopic lymphoid structures is dependent on the expression of lymphoid chemokines, such as stromal cell-derived factor-1/CXCL12, and B cell attracting chemokine-1/CXCL13 and their specific receptors CXCR4 and CXCR5, respectively. [4][5][6] Within the chemokine family, scavenger receptor for phosphatidyl serine and oxidized low-density lipoprotein/CXCL16 and fractalkine/CX3CL1 are exceptional in that they can be found in both membrane-bound and soluble forms. The soluble forms are generated from the former by the proteolytical activities of, for example, a disintegrin and metalloproteinase 10 and a disintegrin and metalloproteinase 17.…”

mentioning

confidence: 99%

Differential CXC and CX3C Chemokine Expression Profiles in Aqueous Humor of Patients With Specific Endogenous Uveitic Entities

El‐Asrar

Berghmans

Al-Obeidan

et al. 2018

Invest. Ophthalmol. Vis. Sci.

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PURPOSE. To determine the levels of the neutrophil chemoattractants CXCL1, CXCL2, CXCL5, CXCL6, and CXCL8, the T helper 1 chemoattractants CXCL9, CXCL10 and CXCL11, the lymphoid chemokines CXCL12 and CXCL13 and the soluble form of the transmembrane chemokines CXCL16 and CX3CL1, in aqueous humor samples from patients with specific uveitic entities.METHODS. Aqueous humor samples from patients with active uveitis associated with Behçet's disease (n ¼ 13), sarcoidosis (n ¼ 8), HLA-B27-related inflammation (n ¼ 12), Vogt-KoyanagiHarada (VKH) disease (n ¼ 12), and healthy controls (n ¼ 9) were assayed with the use of a multiplex assay.RESULTS. All chemoattractant levels were significantly higher in all patients than in the controls. The levels of all neutrophil chemoattractants and CXCL10, CXCL16, and CX3CL1 were significantly higher in nongranulomatous uveitis (Behçet's disease and HLA-B27-associated uveitis) than in granulomatous uveitis (sarcoidosis and VKH disease), whereas the levels of the B cell chemoattractant CXCL13 were significantly higher in granulomatous uveitis than in nongranulomatous uveitis. CXCL13 levels were highest in the patients with VKH disease. CXCL9, CXCL11, and CXCL12 levels did not differ significantly.CONCLUSIONS. Inflammation in nongranulomatous uveitis appears to be driven by neutrophils and T helper 1 lymphocytes, whereas B lymphocytes may contribute to the inflammatory process in granulomatous uveitis, particularly in VKH disease.

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Effects of CXCL13 inhibition on lymphoid follicles in models of autoimmune disease

Cited by 70 publications

References 72 publications

CXCL13 is a plasma biomarker of germinal center activity

CXCL13 is a plasma biomarker of germinal center activity

New insights into B cell biology in systemic lupus erythematosus and Sjögren's syndrome

Differential CXC and CX3C Chemokine Expression Profiles in Aqueous Humor of Patients With Specific Endogenous Uveitic Entities

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