Ectopic lymphoid follicles in progressive multiple sclerosis: From patients to animal models

Zhan, Jiangshan; Kipp, Markus; Han, Wenling; Kaddatz, Hannes

doi:10.1111/imm.13395

Cited by 26 publications

(14 citation statements)

References 126 publications

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“…Based on a previous report (Zrzavy et al, 2017), we performed double‐labeling experiments with anti‐podoplanin and anti‐FDC‐M1 antibodies, both markers for follicular dendritic cells (Köhler, 2010; Lohrberg & Wilting, 2016; Rodda et al, 2018; Schacht et al, 2005; Xie et al, 2008; Yu, Gibson, Pinkus, & Hornick, 2007). These follicular dendritic cells can also be found in certain CNS compartments ( i.e ., the subarachnoid space) under neuroinflammatory conditions (Ludewig et al, 2016; Zhan, Kipp, Han, & Kaddatz, 2021). As demonstrated in Figure 7, we found a clear co‐localization of both follicular dendritic cell markers with TMEM119, suggesting that TMEM119 is not specific for microglia but is also expressed by other cell types outside the CNS.…”

Section: Discussionmentioning

confidence: 99%

Transmembrane protein 119 is neither a specific nor a reliable marker for microglia

Vankriekelsvenne

Chrzanowski

Manzhula

et al. 2022

Glia

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Microglia are the resident innate immune cells of the central nervous system (CNS) parenchyma. To determine the impact of microglia on disease development and progression in neurodegenerative and neuroinflammatory diseases, it is essential to distinguish microglia from peripheral macrophages/monocytes, which are eventually equally recruited. It has been suggested that transmembrane protein 119 (TMEM119) serves as a reliable microglia marker that discriminates resident microglia from blood‐derived macrophages in the human and murine brain. Here, we investigated the validity of TMEM119 as a microglia marker in four in vivo models (cuprizone intoxication, experimental autoimmune encephalomyelitis (EAE), permanent filament middle cerebral artery occlusion (fMCAo), and intracerebral 6‐hydroxydopamine (6‐OHDA) injections) as well as post mortem multiple sclerosis (MS) brain tissues. In all applied animal models and post mortem MS tissues, we found increased densities of ionized calcium‐binding adapter molecule 1+ (IBA1+) cells, paralleled by a significant decrease in TMEM119 expression. In addition, other cell types in peripheral tissues (i.e., follicular dendritic cells and brown adipose tissue) were also found to express TMEM119. In summary, this study demonstrates that TMEM119 is not exclusively expressed by microglia nor does it label all microglia, especially under cellular stress conditions. Since novel transgenic lines have been developed to label microglia using the TMEM119 promotor, downregulation of TMEM119 expression might interfere with the results and should, thus, be considered when working with these transgenic mouse models.

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Section: Discussionmentioning

confidence: 99%

Transmembrane protein 119 is neither a specific nor a reliable marker for microglia

Vankriekelsvenne

Chrzanowski

Manzhula

et al. 2022

Glia

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“…In one of the original articles describing ELFs in patients with secondary progressive MS (SPMS) [ 55 ], the investigators found “a network of follicular dendritic cells producing CXCL13”. A recent review article on ELFs in MS [ 58 ] includes “presence of stromal/follicular dendritic cells expressing CXCL13” as one of the defining features of CNS ELFs in MS. However, ELFs have been generally only present in patients with progressive forms of MS, primarily those with SPMS.…”

Section: Two Logical Candidates For Molecular Biomarkers Based On The...mentioning

confidence: 99%

The Brave New World of Early Treatment of Multiple Sclerosis: Using the Molecular Biomarkers CXCL13 and Neurofilament Light to Optimize Immunotherapy

Pachner

2022

Biomedicines

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Multiple sclerosis (MS) is a highly heterogeneous disease involving a combination of inflammation, demyelination, and CNS injury. It is the leading cause of non-traumatic neurological disability in younger people. There is no cure, but treatments in the form of immunomodulatory drugs (IMDs) are available. Experience over the last 30 years has shown that IMDs, also sometimes called disease-modifying therapies, are effective in downregulating neuroinflammatory activity. However, there are a number of negatives in IMD therapy, including potential for significant side-effects and adverse events, uncertainty about long-term benefits regarding disability outcomes, and very high and increasing financial costs. The two dozen currently available FDA-approved IMDs also are heterogeneous with respect to efficacy and safety, especially long-term safety, and determining an IMD treatment strategy is therefore challenging for the clinician. Decisions about optimal therapy have been particularly difficult in early MS, at the time of the initial clinical demyelinating event (ICDE), at a time when early, aggressive treatment would best be initiated on patients destined to have a highly inflammatory course. However, given the fact that the majority of ICDE patients have a more benign course, aggressive immunosuppression, with its attendant risks, should not be administered to this group, and should only be reserved for patients with a more neuroinflammatory course, a decision that can only be made in retrospect, months to years after the ICDE. This quandary of moderate vs. aggressive therapy facing clinicians would best be resolved by the use of biomarkers that are predictive of future neuroinflammation. Unfortunately, biomarkers, especially molecular biomarkers, have not thus far been particularly useful in assisting clinicians in predicting the likelihood of future neuroinflammation, and thus guiding therapy. However, the last decade has seen the emergence of two highly promising molecular biomarkers to guide therapy in early MS: the CXCL13 index and neurofilament light. This paper will review the immunological and neuroscientific underpinnings of these biomarkers and the data supporting their use in early MS and will propose how they will likely be used to maximize benefit and minimize risk of IMDs in MS patients.

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“…In addition, ectopic lymphoid follicles (ELFs), which resemble germinal center-like structures can be found in the meninges of 40% of the SPMS patients. ELFs were also observed in RRMS and PPMS patients but lack features of more developed follicles such as follicular dendritic cells (FDCs), and distinct T and B cell zones (22,23). ELFs can cause local antigen-specific responses within tissues and thereby support cortical degeneration and clinical disease progression (22).…”

Section: Multiple Sclerosismentioning

confidence: 99%

“…ELFs were also observed in RRMS and PPMS patients but lack features of more developed follicles such as follicular dendritic cells (FDCs), and distinct T and B cell zones (22,23). ELFs can cause local antigen-specific responses within tissues and thereby support cortical degeneration and clinical disease progression (22). Although the causes of MS are still unknown, next to a genetic predisposition, many different environmental factors such as vitamin D deficiency, obesity, smoking, and infection with the Epstein Barr virus (EBV) have been described to play a role in developing MS (2).…”

Section: Multiple Sclerosismentioning

confidence: 99%

Innate Lymphoid Cells - Neglected Players in Multiple Sclerosis

et al. 2022

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Multiple sclerosis (MS) is a highly debilitating autoimmune disease affecting millions of individuals worldwide. Although classically viewed as T-cell mediated disease, the role of innate lymphoid cells (ILC) such as natural killer (NK) cells and ILC 1-3s has become a focal point as several findings implicate them in the disease pathology. The role of ILCs in MS is still not completely understood as controversial findings have been reported assigning them either a protective or disease-accelerating role. Recent findings in experimental autoimmune encephalomyelitis (EAE) suggest that ILCs infiltrate the central nervous system (CNS), mediate inflammation, and have a disease exacerbating role by influencing the recruitment of autoreactive T-cells. Elucidating the detailed role of ILCs and altered signaling pathways in MS is essential for a more complete picture of the disease pathology and novel therapeutic targets. We here review the current knowledge about ILCs in the development and progression of MS and preclinical models of MS and discuss their potential for therapeutic applications.

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Ectopic lymphoid follicles in progressive multiple sclerosis: From patients to animal models

Cited by 26 publications

References 126 publications

Transmembrane protein 119 is neither a specific nor a reliable marker for microglia

Transmembrane protein 119 is neither a specific nor a reliable marker for microglia

The Brave New World of Early Treatment of Multiple Sclerosis: Using the Molecular Biomarkers CXCL13 and Neurofilament Light to Optimize Immunotherapy

Innate Lymphoid Cells - Neglected Players in Multiple Sclerosis

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