Andreas Schulte-Mecklenbeck

Dimethyl fumarate treatment alters circulating T helper cell subsets in multiple sclerosis

Objective: To evaluate the effect of dimethyl fumarate (DMF; Tecfidera, Biogen, Weston, MA) on CD4+ and CD8+ T cell subsets in patients with multiple sclerosis (MS). Methods: Peripheral lymphocyte subsets, including CD4+ and CD8+ memory cells and T helper (TH) cells TH1, TH2, TH17, and peripheral regulatory T cell (pTreg) subpopulations were analyzed before and 6 months after onset of DMF treatment. Results: CD4+ and CD8+ memory T cells were preferentially decreased compared to naive CD4+ and CD8+ T cell populations. Within the CD4+ memory T cell population, frequencies of TH1 cells were decreased, whereas those of TH2 cells were increased and those of TH17 cells remained unaltered. Accordingly, we observed decreased production of interferon γ, granulocyte-macrophage colony-stimulating factor, tumor necrosis factor α, and interleukin (IL)-22 by CD4+ T cells under DMF treatment, whereas the frequency of IL-4- and IL-17A-producing CD4+ T cells remained unchanged. With regard to regulatory T cells, proportions of pTreg increased following DMF treatment. Conclusion: Our data demonstrate that DMF treatment of patients with MS affects predominantly memory T cells accompanied by a shift in TH cell populations, resulting in a shift toward anti-inflammatory responses. These findings indicate that monitoring of memory subsets might enhance vigilance of impaired antiviral immunity and that patients with TH1-driven disease might preferentially benefit from DMF treatment. Classification of Evidence: This study provides Class IV evidence that DMF might preferentially reduce CD4+ and CD8+ memory T cells in MS.

Impaired NK-mediated regulation of T-cell activity in multiple sclerosis is reconstituted by IL-2 receptor modulation

Significance The importance of natural killer (NK) cells in the control of autoimmunity has recently attracted considerable attention. The current study revealed NK cells as additional players in controlling T-cell activity in CNS autoimmunity. NK-mediated control of T-cell activity in multiple sclerosis (MS) is dysregulated and caused by impaired DNAX accessory molecule-1/CD155 interaction between NK cells and CD4+ T cells. Therapeutic immune modulation of the IL-2 receptor with daclizumab, which has just successfully passed a phase III study in relapsing-remitting MS, not only enhances the cytolytic activity of NK cells but also restores defective NK-mediated immune regulation by increasing the proportion of CD155-expressing CD4+ T cells, thus rendering CD4+ T cells most likely more sensitive to NK-mediated lysis. Multiple sclerosis (MS) is a chronic inflammatory autoimmune disease of the central nervous system (CNS) resulting from a breakdown in peripheral immune tolerance. Although a beneficial role of natural killer (NK)-cell immune-regulatory function has been proposed, it still needs to be elucidated whether NK cells are functionally impaired as part of the disease. We observed NK cells in active MS lesions in close proximity to T cells. In accordance with a higher migratory capacity across the blood–brain barrier, CD56bright NK cells represent the major intrathecal NK-cell subset in both MS patients and healthy individuals. Investigating the peripheral blood and cerebrospinal fluid of MS patients treated with natalizumab revealed that transmigration of this subset depends on the α4β1 integrin very late antigen (VLA)-4. Although no MS-related changes in the migratory capacity of NK cells were observed, NK cells derived from patients with MS exhibit a reduced cytolytic activity in response to antigen-activated CD4+ T cells. Defective NK-mediated immune regulation in MS is mainly attributable to a CD4+ T-cell evasion caused by an impaired DNAX accessory molecule (DNAM)-1/CD155 interaction. Both the expression of the activating NK-cell receptor DNAM-1, a genetic alteration consistently found in MS-association studies, and up-regulation of the receptor’s ligand CD155 on CD4+ T cells are reduced in MS. Therapeutic immune modulation of IL-2 receptor restores impaired immune regulation in MS by increasing the proportion of CD155-expressing CD4+ T cells and the cytolytic activity of NK cells.

Regulatory Functions of Natural Killer Cells in Multiple Sclerosis

There is increasing evidence that natural killer (NK) cells exhibit regulatory features. Among them, CD56bright NK cells have been suggested to play a major role in controlling T cell responses and maintaining homeostasis. Dysfunction in NK cell-mediated regulatory features has been recently described in untreated multiple sclerosis (MS), suggesting a contribution to MS pathogenesis. Moreover, biological disease-modifying treatments effective in MS apparently enhance the frequencies and/or regulatory function of NK cells, further pointing toward an immunoprotective role of NK cells in MS. Here, we summarize the current knowledge on the regulatory functions of NK cells, based on their interactions with other cells belonging to the innate compartment, as well as with adaptive effector cells. We review the more recent data reporting disruption of NK cell/T cell interactions in MS and discuss how disease-modifying treatments for MS affect NK cells.

Alemtuzumab treatment alters circulating innate immune cells in multiple sclerosis

Objective: To characterize changes in myeloid and lymphoid innate immune cells in patients with relapsing-remitting multiple sclerosis (MS) during a 6-month follow-up after alemtuzumab treatment. Methods: Circulating innate immune cells including myeloid cells and innate lymphoid cells (ILCs) were analyzed before and 6 and 12 months after onset of alemtuzumab treatment. Furthermore, a potential effect on granulocyte-macrophage colony-stimulating factor (GM-CSF) and interleukin (IL)–23 production by myeloid cells and natural killer (NK) cell cytolytic activity was determined. Results: In comparison to CD4+ T lymphocytes, myeloid and lymphoid innate cell subsets of patients with MS expressed significantly lower amounts of CD52 on their cell surface. Six months after CD52 depletion, numbers of circulating plasmacytoid dendritic cells (DCs) and conventional DCs were reduced compared to baseline. GM-CSF and IL-23 production in DCs remained unchanged. Within the ILC compartment, the subset of CD56bright NK cells specifically expanded under alemtuzumab treatment, but their cytolytic activity did not change. Conclusions: Our findings demonstrate that 6 months after alemtuzumab treatment, specific DC subsets are reduced, while CD56bright NK cells expanded in patients with MS. Thus, alemtuzumab specifically restricts the DC compartment and expands the CD56bright NK cell subset with potential immunoregulatory properties in MS. We suggest that remodeling of the innate immune compartment may promote long-term efficacy of alemtuzumab and preserve immunocompetence in patients with MS.

Neurocognitive decline in HIV patients is associated with ongoing T-cell activation in the cerebrospinal fluid.

HIV‐associated neurocognitive disorders (HAND) remain a challenge despite combination antiretroviral therapy (cART). Immune cell activation has been implicated to play a major role in the development of HAND.

Distinct pattern of lesion distribution in multiple sclerosis is associated with different circulating T-helper and helper-like innate lymphoid cell subsets

Background: Distinct lesion topography in relapsing-remitting multiple sclerosis (RRMS) might be due to different antigen presentation and/or trafficking routes of immune cells into the central nervous system (CNS). Objective: To investigate whether distinct lesion patterns in multiple sclerosis (MS) might be associated with a predominance of distinct circulating T-helper cell subset as well as their innate counterparts. Methods: Flow cytometric analysis of lymphocytes derived from the peripheral blood of patients with exclusively cerebral (n = 20) or predominantly spinal (n = 12) disease manifestation. Results: Patients with exclusively cerebral or preferential spinal lesion manifestation were associated with increased proportions of circulating granulocyte-macrophage colony-stimulating factor (GM-CSF) producing TH1 cells or interleukin (IL)-17-producing TH17 cells, respectively. In contrast, proportions of peripheral IL-17/IL-22-producing lymphoid tissue inducer (LTi), the innate counterpart of TH17 cells, were enhanced in RRMS patients with exclusively cerebral lesion topography. Conclusions: Distinct T-helper and T-helper-like innate lymphoid cell (ILC) subsets are associated with different lesion topography in RRMS.

B7-H1 shapes T-cell–mediated brain endothelial cell dysfunction and regional encephalitogenicity in spontaneous CNS autoimmunity

Significance A crucial step in the pathogenesis of autoimmune diseases, such as multiple sclerosis (MS), is transmigration of pathogenic T cells across the blood–brain barrier. These T cells mediate inflammation and subsequent lesion formation in the CNS. However, molecular mechanisms underlying lesion distribution and formation are not well understood. We here show that genetic ablation of a single immunoregulatory molecule on T cells, B7-homolog 1 (B7-H1), causes local endothelial dysfunction and determines lesion topography in a spontaneous mouse model of CNS autoimmunity. These findings can lead to new therapeutic approaches in targeting pathogenic T cell responses in MS. Molecular mechanisms that determine lesion localization or phenotype variation in multiple sclerosis are mostly unidentified. Although transmigration of activated encephalitogenic T cells across the blood–brain barrier (BBB) is a crucial step in the disease pathogenesis of CNS autoimmunity, the consequences on brain endothelial barrier integrity upon interaction with such T cells and subsequent lesion formation and distribution are largely unknown. We made use of a transgenic spontaneous mouse model of CNS autoimmunity characterized by inflammatory demyelinating lesions confined to optic nerves and spinal cord (OSE mice). Genetic ablation of a single immune-regulatory molecule in this model [i.e., B7-homolog 1 (B7-H1, PD-L1)] not only significantly increased incidence of spontaneous CNS autoimmunity and aggravated disease course, especially in the later stages of disease, but also importantly resulted in encephalitogenic T-cell infiltration and lesion formation in normally unaffected brain regions, such as the cerebrum and cerebellum. Interestingly, B7-H1 ablation on myelin oligodendrocyte glycoprotein-specific CD4+ T cells, but not on antigen-presenting cells, amplified T-cell effector functions, such as IFN-γ and granzyme B production. Therefore, these T cells were rendered more capable of eliciting cell contact-dependent brain endothelial cell dysfunction and increased barrier permeability in an in vitro model of the BBB. Our findings suggest that a single immune-regulatory molecule on T cells can be ultimately responsible for localized BBB breakdown, and thus substantial changes in lesion topography in the context of CNS autoimmunity.

The two‐pore domain K2P channel TASK2 drives human NK‐cell proliferation and cytolytic function

Natural killer (NK) cells are a subset of cytotoxic lymphocytes that recognize and kill tumor‐ and virus‐infected cells without prior stimulation. Killing of target cells is a multistep process including adhesion to target cells, formation of an immunological synapse, and polarization and release of cytolytic granules. The role of distinct potassium channels in this orchestrated process is still poorly understood. The current study reveals that in addition to the voltage‐gated KV1.3 and the calcium‐activated KCa3.1 channels, human NK cells also express the two‐pore domain K2P channel TASK2 (TWIK‐related acid‐sensitive potassium channel). Expression of Task2 varies among NK‐cell subsets and depends on their differentiation and activation state. Despite its different expression in TASK2highCD56brightCD16− and TASK2lowCD56dimCD16+ NK cells, TASK2 is involved in cytokine‐induced proliferation and cytolytic function of both subsets. TASK2 is crucial for leukocyte functional antigen (LFA‐1) mediated adhesion of both resting and cytokine‐activated NK cells to target cells, an early step in killing of target cells. With regard to the following mechanism, TASK2 plays a role in release of cytotoxic granules by resting, but not IL‐15‐induced NK cells. Taken together, our data exhibit two‐pore potassium channels as important players in NK‐cell activation and effector function.

Reply to Liu et al.: Haplotype matters: CD226 polymorphism as a potential trigger for impaired immune regulation in multiple sclerosis.

Multiple sclerosis (MS) is an autoimmune disease of the central nervous system, which results from a breakdown in peripheral tolerance driven by genetic and environmental factors. The activating receptor DNAM-1 (DNAX accessory molecule-1, CD226) seems to be crucial in both NK-cell (1) and Foxp3+ (forkhead box protein-3) regulatory T-cell (Treg) (2) -mediated control of T-cell activity, suggesting that CD226-mediated immune regulation is conserved among innate and adaptive immune-regulatory networks. Concomitant with a disease-related impaired immune-regulatory function, NK cells (1) and Treg (2) derived from MS patients exhibit a reduced cell surface expression of CD226. Thus, MS-related reduced CD226 expression likely decreases their suppressive capacity. Genome-wide association studies revealed susceptibility variants of polymorphisms in the CD226 gene, namely rs727088G and rs763361T, in distinct autoimmune diseases, including MS (3⇓–5). Recently, Liu et al. investigated whether rs763361 effects CD226 expression (6). PhenoScanner (www.phenoscanner.medschl.cam.ac.uk/phenoscanner) database analysis revealed that rs763361 polymorphism controls expression of CD226 (6). Further analysis by this group demonstrates that rs763361T … [↵][1]2To whom correspondence may be addressed. Email: Catharina.Gross{at}ukmuenster.de or heinz.wiendl{at}ukmuenster.de. [1]: #xref-corresp-1-1

Treating refractory post-herpetic anti-N-methyl-d-aspartate receptor encephalitis with rituximab

Abstract Herpes simplex virus-1 has been identified as the trigger factor in certain cases of NMDA-receptor autoimmune encephalitis. We report on a 67-year-old female patient, who was severely affected by post-herpetic NMDA-receptor autoimmune encephalitis. Her symptoms did not improve under methylprednisolone pulse therapy and plasma exchange under acyclovir prophylaxis. She received protein A immunoadsorption and a long-term immunosuppression with rituximab. Under treatment, activated T-cells as well as B- and plasma cells decreased in peripheral blood and cerebrospinal fluid, and anti-NMDA-R IgG titers in serum and cerebrospinal fluid declined with near complete cessation of intrathecal autoantibody synthesis. The patient regained near complete independence and profoundly improved on formal neuropsychological assessment. Despite reduction of antiviral defense through of lowered activated T cells and concomitantly decreasing HSV-specific IgG antibodies, no evidence of viral reactivation was detected.