Dissection of complement and Fc-receptor-mediated pathomechanisms of autoantibodies to myelin oligodendrocyte glycoprotein.

Autoantibodies against myelin oligodendrocyte glycoprotein (MOG) have recently been established to define a new disease entity, MOG-antibody-associated disease (MOGAD), which is clinically overlapping with multiple sclerosis. MOG-specific antibodies (Abs) from patients are pathogenic, but the precise effector mechanisms are currently still unknown and no therapy is approved for MOGAD. Here, we determined the contributions of complement and Fc-receptor (FcR)-mediated effects in the pathogenicity of MOG-Abs. Starting from a recombinant anti-MOG (mAb) with human IgG1 Fc, we established MOG-specific mutant mAbs with differential FcR and C1q binding. We then applied selected mutants of this MOG-mAb in two animal models of experimental autoimmune encephalomyelitis. First, we found MOG-mAb-induced demyelination was mediated by both complement and FcRs about equally. Second, we found that MOG-Abs enhanced activation of cognate MOG-specific T cells in the central nervous system (CNS), which was dependent on FcR-, but not C1q-binding. The identification of complement-dependent and -independent pathomechanisms of MOG-Abs has implications for therapeutic strategies in MOGAD.

Features of Isoforms of Human Soluble TACI.

The BAFF/APRIL-system with the two cytokines BAFF and APRIL and their three receptors, transmembrane activator and CAML interactor (TACI), BAFF receptor, and B-cell maturation Ag, is important for B cell maintenance. The BAFF/APRIL system is a therapeutic target in B cell-derived malignancies and autoimmune diseases. However, unexpected outcomes of clinical trials with atacicept (TACI-Fc) underline our incomplete understanding of this system. Shedding of the three receptors is one important regulatory element. In humans, TACI exists in two isoforms generated through alternative splicing in their extracellular portion: TACI-long (l) has two cysteine-rich domains, whereas TACI-short (s) lacks the first low-affinity one. In this study, we discriminated soluble (s) forms of TACI-l and TACI-s with newly generated mAbs and found that both were spontaneously released from activated human B cells, with a predominance of sTACI-l. Furthermore, sTACI-l was also the dominant isoform in human serum. Vaccination with the mRNA vaccine from BioNTech does not significantly affect the serum levels of sTACI-l. Both TACI-s and TACI-l were shed by a disintegrin and metalloproteinase domain-containing protein 10. TACI-l and TACI-s formed homo- and hetero-oligomers in soluble and membrane-bound forms. Both sTACI-l and sTACI-s acted as decoy receptors for BAFF, but only sTACI-l also efficiently inhibited APRIL. Dimerization of sTACI-l enhanced its decoy functions only slightly. Together, we extend our knowledge of the complexity of the BAFF/APRIL system by identifying and characterizing the two soluble isoforms of TACI.

Anti-pan-neurofascin antibodies induce subclass-related complement activation and nodo-paranodal damage.

Autoimmune neuropathy associated with antibodies against pan-neurofascin is a new subtype of nodo-paranodopathy. It is relevant because it is associated with high morbidity and mortality. Affected patients often require intensive care unit treatment for several months, and data on the reversibility and long-term prognosis are limited. The pathogenicity including IgG subclass-associated mechanisms has not been unravelled, nor directly compared to anti-neurofascin-155 IgG4-related pathology. Understanding the underlying pathology might have a direct impact on treatment of these severely affected patients. By a multicentre combined prospective and retrospective approach, we provide clinical data of a large cohort of patients with anti-neurofascin-associated neuropathy (n = 18) including longitudinal titre and neurofilament light chain assessment via Ella® and relate clinical data to in vitro pathogenicity studies of anti-neurofascin antibodies. We assessed antibody binding characteristics and the pathogenic effects of anti-pan-neurofascin versus neurofascin-155 antibodies on living myelinating dorsal root ganglia co-cultures. Additionally, we analysed the IgG subclass profile and the complement binding capacity and effector functions considering the effects of intravenous immunoglobulin preparations via enzyme-linked immunosorbent and cell-based assays. In contrast to chronic neurofascin-155 IgG4-associated neuropathy, anti-pan-neurofascin-associated disease presented with a high morbidity and mortality, but as a monophasic and potentially reversible disorder. During follow-up, antibodies were no longer detectable in 8 of 11 patients. Anti-pan-neurofascin had direct access to the nodes of Ranvier in myelinating cultures titre-dependently, most probably inducing this severe phenotype. Antibody preincubation led to impaired paranode formation, destruction of paranodal architecture and alterations on paranodal myelin and sensory neurons in the cultures, with more severe effects than neurofascin-155 antibodies. Besides IgG4, subclass IgG3 was detected and associated with complement binding and cytotoxic effects in vitro. As a possible correlate of axonal damage in vivo, we detected highly increased serum neurofilament light chain levels (sNF-L), correlating to serum C3a. Still, sNF-L was not identified as a marker for poor prognosis, but rather as an intra- and interindividual marker for acuteness, severity and course, with a strong decrease during recovery. Our data provide evidence that anti-pan-neurofascin antibodies directly attack the node and induce severe and acute, but potentially reversible, nodo-paranodal pathology, possibly involving complement-mediated mechanisms. Screening for autoantibodies thus is crucial to identify this subset of patients who benefit from early antibody-depleting therapy. Titre and sNF-L might serve as valuable follow-up parameters. The prospect of a favourable outcome has high relevance for physicians, patients and relatives during months of critical care.

Pathomechanisms in demyelination and astrocytopathy: autoantibodies to AQP4, MOG, GFAP, GRP78 and beyond.

PURPOSE OF REVIEW: The purpose of this review is to highlight the recently emerging pathomechanisms of diseases associated with autoantibodies to AQP4, MOG, GFAP, GRP78 and further novel targets. We discuss novel biomarkers and therapeutic approaches. RECENT FINDINGS: Although complement-mediated cytotoxicity (CDC) is regarded as the major effector mechanism for AQP4-IgG in neuromyelitis optica spectrum disorders (NMOSD), recent studies helped to understand the relevance of complement-independent effector mechanisms. For MOG-IgG mediated diseases the role of CDC is less clear. MOG-IgG may trigger a tightly controlled FcR and BTK-driven microglia proliferative response in MOG-antibody-associated diseases. Differences of antibody-mediated tissue damage may reflect differential response to therapy. In addition, antibodies to GFAP, GRP78 and further novel targets have been implicated in demyelination and astrocytopathy. SUMMARY: Elucidating the whole spectrum of effector functions in diseases mediated by AQP4-IgG and MOG-IgG and understanding the role of additional novel autoantibodies involved in demyelination and astrocytopathy may guide further novel treatment decisions.

Fingolimod Profoundly Reduces Frequencies and Alters Subset Composition of Circulating T Follicular Helper Cells in Multiple Sclerosis Patients.

Fingolimod is an effective treatment for relapsing-remitting multiple sclerosis. It is well established that fingolimod, a modulator of the sphingosine-1-phosphate pathway, restrains the egress of CCR7+ lymphocytes from lymphatic tissues into the blood, thus resulting in reduced lymphocyte counts in peripheral blood. CXCR5+ T follicular helper (Tfh) cells provide help to B cells, are essential for the generation of potent Ab responses, and have been shown to be critically involved in the pathogenesis of several autoimmune diseases. Besides lymphoid tissue-resident Tfh cells, CXCR5+ circulating Tfh (cTfh) cells have been described in the blood, their numbers correlating with the magnitude of Tfh cells in lymphoid tissues. Although the effect of fingolimod on circulating lymphocyte subsets has been established, its effect on cTfh cells remains poorly understood. In this study, we found that although fingolimod strongly and disproportionally reduced cTfh cell frequencies, frequencies of activated cTfh cells were increased, and the composition of the cTfh cell pool was skewed toward a cTfh1 cell phenotype. The circulating T follicular regulatory cell subset and CXCR5+ CD8+ T cell frequencies were also strongly and disproportionally decreased after fingolimod treatment. In contrast, relative frequencies of CXCR5- memory Th cells as well as regulatory T and B cells were increased. In summary, these data provide new insights into fingolimod-induced compositional changes of lymphocyte populations in the blood, in particular cTfh cells, and thus contribute to a better understanding of the mechanism of action of fingolimod in multiple sclerosis patients.

Features of MOG required for recognition by patients with MOG antibody-associated disorders.

Antibodies to myelin oligodendrocyte glycoprotein (MOG-Abs) define a distinct disease entity. Here we aimed to understand essential structural features of MOG required for recognition by autoantibodies from patients. We produced the N-terminal part of MOG in a conformationally correct form; this domain was insufficient to identify patients with MOG-Abs by ELISA even after site-directed binding. This was neither due to a lack of lipid embedding nor to a missing putative epitope at the C-terminus, which we confirmed to be an intracellular domain. When MOG was displayed on transfected cells, patients with MOG-Abs recognized full-length MOG much better than its N-terminal part with the first hydrophobic domain (P < 0.0001). Even antibodies affinity-purified with the extracellular part of MOG recognized full-length MOG better than the extracellular part of MOG after transfection. The second hydrophobic domain of MOG enhanced the recognition of the extracellular part of MOG by antibodies from patients as seen with truncated variants of MOG. We confirmed the pivotal role of the second hydrophobic domain by fusing the intracellular part of MOG from the evolutionary distant opossum to the human extracellular part; the chimeric construct restored the antibody binding completely. Further, we found that in contrast to 8-18C5, MOG-Abs from patients bound preferentially as F(ab')2 rather than Fab. It was previously found that bivalent binding of human IgG1, the prominent isotype of MOG-Abs, requires that its target antigen is displayed at a distance of 13-16 nm. We found that, upon transfection, molecules of MOG did not interact so closely to induce a Förster resonance energy transfer signal, indicating that they are more than 6 nm apart. We propose that the intracellular part of MOG holds the monomers apart at a suitable distance for bivalent binding; this could explain why a cell-based assay is needed to identify MOG-Abs. Our finding that MOG-Abs from most patients require bivalent binding has implications for understanding the pathogenesis of MOG-Ab associated disorders. Since bivalently bound antibodies have been reported to only poorly bind C1q, we speculate that the pathogenicity of MOG-Abs is mostly mediated by other mechanisms than complement activation. Therefore, therapeutic inhibition of complement activation should be less efficient in MOG-Ab associated disorders than in patients with antibodies to aquaporin-4 .

To cut or not to cut: New rules for proteolytic shedding of membrane proteins.

Sheddases are specialized proteases that control the abundance and function of membrane proteins by cleaving their substrate's extracellular domain (ectodomain), a process known as shedding. Hundreds of shedding substrates have been identified, but little is known about the mechanisms that govern ectodomain shedding. Iwagishi et al. now report that negatively charged amino acids in the membrane-proximal juxtamembrane domain of substrates make them resistant to shedding by the metalloprotease ADAM17. These findings will help researchers better understand the regulation of shedding and may aid in the development of drugs targeting sheddases.

Archeological neuroimmunology: resurrection of a pathogenic immune response from a historical case sheds light on human autoimmune encephalomyelitis and multiple sclerosis.

Aim of our study was to identify the target auto-antigen in the central nervous system recognized by the immune system of a unique patient, who died more than 60 years ago from a disease with pathological changes closely resembling multiple sclerosis (MS), following a misguided immunization with lyophilized calf brain tissue. Total mRNA was isolated from formaldehyde fixed and paraffin embedded archival brain tissue containing chronic active inflammatory demyelinating lesions with inflammatory infiltrates rich in B-lymphocytes and plasma cells. Analysis of the transcriptome by next generation sequencing and reconstruction of the dominant antibody by bioinformatic tools revealed the presence of one strongly expanded B-cell clone, producing an autoantibody against a conformational epitope of myelin oligodendrocytes glycoprotein (MOG), similar to that recognized by the well characterized monoclonal anti-MOG antibody 8-18C5. The reconstructed antibody induced demyelination after systemic or intrathecal injection into animals with T-cell mediated encephalomyelitis. Our study suggests that immunization with bovine brain tissue in humans may-in a small subset of patients-induce a disease with an intermediate clinical and pathological presentation between MS and MOG-antibody associated inflammatory demyelinating disease (MOGAD).

Shedding of BAFF/APRIL Receptors Controls B Cells.

Proteolytic shedding of the receptors BCMA, TACI, and BAFFR reduces their cell-surface expression and ligand-mediated survival of B cell subsets. This shedding is executed by protease γ-secretase or by metalloproteases, and is partially dependent on ligand binding and receptor interactions. Shed receptors may serve as biomarkers for autoimmunity and lymphoma.

MicroRNAs in gray and white matter multiple sclerosis lesions: impact on pathophysiology.

Multiple sclerosis (MS) is a chronic disease of the CNS, hallmarked by inflammation and demyelination. Early stages of the disease frequently show active lesions containing numerous foamy macrophages and inflammatory cells. Disease progression is highlighted by increasing numbers of mixed active/inactive or inactive lesions showing sparse inflammation and pronounced astrogliosis. Furthermore, gray matter lesions increase in number and extent during disease progression. MicroRNAs (miRNAs) comprise a group of several thousand (in humans more than 2000), small non-coding RNA molecules with a fundamental influence on about one-third of all protein-coding genes. Furthermore, miRNAs have been detected in body fluids, including spinal fluid, and they are assumed to participate in intercellular communications. Several studies have determined miRNA profiles from dissected white and gray matter lesions of autoptic MS patients. In this review, we summarize in detail the current knowledge of individual miRNAs in gray and white matter lesions of MS patients and present the concepts of MS tissue lesion development based on the altered miRNA profiles. © 2020 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.

Novel insights into pathophysiology and therapeutic possibilities reveal further differences between AQP4-IgG- and MOG-IgG-associated diseases.

PURPOSE OF REVIEW: This review summarizes recent insights into the pathogenesis and therapeutic options for patients with MOG- or AQP4-antibodies. RECENT FINDINGS: Although AQP4-IgG are linked to NMOSD, MOG-IgG-associated diseases (MOGAD) include a broader clinical spectrum of autoimmune diseases of the central nervous system (CNS). Details of membrane assembly of AQP4-IgG required for complement activation have been uncovered. Affinity-purified MOG-IgG from patients were shown to be pathogenic by induction of demyelination when the blood--brain barrier (BBB) was breached and by enhancement of activation of cognate T cells. A high-affinity AQP4-IgG, given peripherally, could induce NMOSD-like lesions in rats in the absence of BBB breach. Circulating AQP4-specific and MOG-specific B cells were identified and suggest differences in origin of MOG-antibodies or AQP4-antibodies. Patients with MOG-IgG show a dichotomy concerning circulating MOG-specific B cells; whether this is related to differences in clinical response of anti-CD20 therapy remains to be analyzed. Clinical trials of AQP4-IgG-positive NMOSD patients showed success with eculizumab (preventing cleavage of complement factor C5, thereby blocking formation of chemotactic C5a and membrane attack complex C9neo), inebilizumab (depleting CD19 + B cells), and satralizumab (anti-IL-6R blocking IL-6 actions). SUMMARY: New insights into pathological mechanisms and therapeutic responses argue to consider NMOSD with AQP4-IgG and MOGAD as separate disease entities.

Abundant glutamic acid decarboxylase (GAD)-reactive B cells in gad-antibody-associated neurological disorders.

High levels of antibodies against glutamic acid decarboxylase (GAD) are observed in patients with different neurological disorders, but cells producing these autoantibodies are largely unexplored. We detect circulating GAD-reactive B cells in peripheral blood that readily differentiate into antibody-producing cells. These cells are highly elevated in most patients with GAD-antibody-associated disorders (n = 15) compared to controls (n = 19). They mainly produce GAD65 antibodies of the IgG1 and IgG4 subclasses and are as abundant as B cells reactive for common recall antigens. Bone marrow cells represent an additional source of GAD antibodies. The identification of GAD-antibody-producing cells has implications for the selection of cell-specific biologics. ANN NEUROL 2019;85:448-454.

Anti-MOG antibody-associated disorders: differences in clinical profiles and prognosis in Japan and Germany.

BACKGROUND: Neurological disorders with IgG antibodies against myelin-oligodendrocyte glycoprotein (MOG-IgG) have been increasingly recognised as a new type of neuroinflammatory disorder. OBJECTIVE: The study aimed to identify regional and ethnic differences in clinical profiles of MOG-IgG-associated disorders between East Asian (Japanese) and Caucasian (German) patients. METHODS: Demographic, clinical and therapeutic data from 68 MOG-IgG-positive adults were collected (Japanese, n=44; German, n=24). RESULTS: Age and sex were similar between cohorts, with optic neuritis occurring most frequently at onset (Japanese: 61%; German: 58%). However, Japanese patients had a lower annualised relapse rate (0.4 vs 0.8, p=0.019; no relapse, 64% vs 25%, p=0.002) and lower Expanded Disability Status Scale score at the last visit (1.0 vs 2.0; p=0.008), despite similar follow-up periods (mean, 73.9 months vs 73.4 months), than those of German patients, respectively. Cerebral syndromes were more common (27% vs 4%; p=0.021) and myelitis less common (21% vs 50%; p=0.012) in Japanese than in German patients, respectively. Japanese patients were more commonly treated with long-term corticosteroids (73%), whereas German patients were more commonly treated with rituximab or other immunosuppressants (63%). CONCLUSIONS: Among patients with MOG-IgG, Japanese tended to have a monophasic milder disease, whereas the majority of German patients had a relapsing course and more frequent myelitis, findings compatible with neuromyelitis optica spectrum disorder. Although the attack-prevention treatment regimens were considerably different, genetic and environmental factors may be important to determine clinical phenotypes and disease activity.

IL-35-producing B cells are critical regulators of immunity during autoimmune and infectious diseases.

B lymphocytes have critical roles as positive and negative regulators of immunity. Their inhibitory function has been associated primarily with interleukin 10 (IL-10) because B-cell-derived IL-10 can protect against autoimmune disease and increase susceptibility to pathogens. Here we identify IL-35-producing B cells as key players in the negative regulation of immunity. Mice in which only B cells did not express IL-35 lost their ability to recover from the T-cell-mediated demyelinating autoimmune disease experimental autoimmune encephalomyelitis (EAE). In contrast, these mice displayed a markedly improved resistance to infection with the intracellular bacterial pathogen Salmonella enterica serovar Typhimurium as shown by their superior containment of the bacterial growth and their prolonged survival after primary infection, and upon secondary challenge, compared to control mice. The increased immunity found in mice lacking IL-35 production by B cells was associated with a higher activation of macrophages and inflammatory T cells, as well as an increased function of B cells as antigen-presenting cells (APCs). During Salmonella infection, IL-35- and IL-10-producing B cells corresponded to two largely distinct sets of surface-IgM(+)CD138(hi)TACI(+)CXCR4(+)CD1d(int)Tim1(int) plasma cells expressing the transcription factor Blimp1 (also known as Prdm1). During EAE, CD138(+) plasma cells were also the main source of B-cell-derived IL-35 and IL-10. Collectively, our data show the importance of IL-35-producing B cells in regulation of immunity and highlight IL-35 production by B cells as a potential therapeutic target for autoimmune and infectious diseases. This study reveals the central role of activated B cells, particularly plasma cells, and their production of cytokines in the regulation of immune responses in health and disease.

Optical coherence tomography in myelin-oligodendrocyte-glycoprotein antibody-seropositive patients: a longitudinal study.

BACKGROUND: Serum antibodies against myelin-oligodendrocyte-glycoprotein (MOG-IgG) are detectable in a proportion of patients with acute or relapsing neuroinflammation. It is unclear, if neuro-axonal damage occurs only in an attack-dependent manner or also progressively. Therefore, this study aimed to investigate longitudinally intra-retinal layer changes in eyes without new optic neuritis (ON) in MOG-IgG-seropositive patients. METHODS: We included 38 eyes of 24 patients without ON during follow-up (F/U) [median years (IQR)] 1.9 (1.0-2.2) and 56 eyes of 28 age- and sex-matched healthy controls (HC). The patient group's eyes included 18 eyes without (EyeON-) and 20 eyes with history of ON (EyeON+). Using spectral domain optical coherence tomography (OCT), we acquired peripapillary retinal nerve fiber layer thickness (pRNFL) and volumes of combined ganglion cell and inner plexiform layer (GCIP), inner nuclear layer (INL), and macular volume (MV). High-contrast visual acuity (VA) was assessed at baseline. RESULTS: At baseline in EyeON-, pRNFL (94.3 ± 15.9 µm, p = 0.36), INL (0.26 ± 0.03 mm3, p = 0.11), and MV (2.34 ± 0.11 mm3, p = 0.29) were not reduced compared to HC; GCIP showed thinning (0.57 ± 0.07 mm3; p = 0.008), and VA was reduced (logMAR 0.05 ± 0.15 vs. - 0.09 ± 0.14, p = 0.008) in comparison to HC. Longitudinally, we observed pRNFL thinning in models including all patient eyes (annual reduction - 2.20 ± 4.29 µm vs. - 0.35 ± 1.17 µm, p = 0.009) in comparison to HC. Twelve EyeON- with other than ipsilateral ON attacks ≤ 6 months before baseline showed thicker pRNFL at baseline and more severe pRNFL thinning in comparison to 6 EyeON- without other clinical relapses. CONCLUSIONS: We observed pRNFL thinning in patients with MOG-IgG during F/U, which was not accompanied by progressive GCIP reduction. This effect could be caused by a small number of EyeON- with other than ipsilateral ON attacks within 6 months before baseline. One possible interpretation could be a reduction of the swelling, which could mean that MOG-IgG patients show immune-related swelling in the CNS also outside of an attack's target area.

Myelin oligodendrocyte glycoprotein revisited-sensitive detection of MOG-specific T-cells in multiple sclerosis.

Autoreactive CD4+ T-cells are believed to be a main driver of multiple sclerosis (MS). Myelin oligodendrocyte glycoprotein (MOG) is considered an autoantigen, yet doubted in recent years. The reason is in part due to low frequency and titers of MOG autoantibodies and the challenge to detect MOG-specific T-cells. In this study we aimed to analyze T-cell reactivity and frequency utilizing a novel method for detection of antigen-specific T-cells with bead-bound MOG as stimulant. Peripheral blood mononuclear cells (PBMCs) from natalizumab treated persons with MS (n = 52) and healthy controls (HCs) (n = 24) were analyzed by IFNγ/IL-22/IL-17A FluoroSpot. A higher number of IFNγ (P = 0.001), IL-22 (P = 0.003), IL-17A (P < 0.0001) as well as double and triple cytokine producing MOG-specific T-cells were detected in persons with MS compared to HCs. Of the patients, 46.2-59.6% displayed MOG-reactivity. Depletion of CD4+ T-cells or monocytes or blocking HLA-DR completely eliminated the MOG specific response. Anti-MOG antibodies did not correlate with T-cell MOG-responses. In conclusion, we present a sensitive method to detect circulating autoreactive CD4+ T-cells producing IFNγ, IL-22 or IL-17A using MOG as a model antigen. Further, we demonstrate that MOG-specific T-cells are present in approximately half of persons with MS.

Pathogenicity of human antibodies against myelin oligodendrocyte glycoprotein.

OBJECTIVE: Autoantibodies against myelin oligodendrocyte glycoprotein (MOG) occur in a proportion of patients with inflammatory demyelinating diseases of the central nervous system (CNS). We analyzed their pathogenic activity by affinity-purifying these antibodies (Abs) from patients and transferring them to experimental animals. METHODS: Patients with Abs to MOG were identified by cell-based assay. We determined the cross-reactivity to rodent MOG and the recognized MOG epitopes. We produced the correctly folded extracellular domain of MOG and affinity-purified MOG-specific Abs from the blood of patients. These purified Abs were used to stain CNS tissue and transferred in 2 models of experimental autoimmune encephalomyelitis. Animals were analyzed histopathologically. RESULTS: We identified 17 patients with MOG Abs from our outpatient clinic and selected 2 with a cross-reactivity to rodent MOG; both had recurrent optic neuritis. Affinity-purified Abs recognized MOG on transfected cells and stained myelin in tissue sections. The Abs from the 2 patients recognized different epitopes on MOG, the CC' and the FG loop. In both patients, these Abs persisted during our observation period of 2 to 3 years. The anti-MOG Abs from both patients were pathogenic upon intrathecal injection in 2 different rat models. Together with cognate MOG-specific T cells, these Abs enhanced T-cell infiltration; together with myelin basic protein-specific T cells, they induced demyelination associated with deposition of C9neo, resembling a multiple sclerosis type II pathology. INTERPRETATION: MOG-specific Abs affinity purified from patients with inflammatory demyelinating disease induce pathological changes in vivo upon cotransfer with myelin-reactive T cells, suggesting that these Abs are similarly pathogenic in patients. Ann Neurol 2018;84:315-328.

Human Plasmacytoid Dendritic Cells Display and Shed B Cell Maturation Antigen upon TLR Engagement.

The BAFF-APRIL system is best known for its control of B cell homeostasis, and it is a target of therapeutic intervention in autoimmune diseases and lymphoma. By analyzing the expression of the three receptors of this system, B cell maturation Ag (BCMA), transmembrane activator and CAML interactor, and BAFF receptor, in sorted human immune cell subsets, we found that BCMA was transcribed in plasmacytoid dendritic cells (pDCs) in both blood and lymphoid tissue. Circulating human pDCs contained BCMA protein without displaying it on the cell surface. After engagement of TLR7/8 or TLR9, BCMA was detected also on the cell surface of pDCs. The display of BCMA on the surface of human pDCs was accompanied by release of soluble BCMA (sBCMA); inhibition of γ-secretase enhanced surface expression of BCMA and reduced the release of sBCMA by pDCs. In contrast with human pDCs, murine pDCs did not express BCMA, not even after TLR9 activation. In this study, we extend the spectrum of BCMA expression to human pDCs. sBCMA derived from pDCs might determine local availability of its high-affinity ligand APRIL, because sBCMA has been shown to function as an APRIL-specific decoy. Further, therapeutic trials targeting BCMA in patients with multiple myeloma should consider possible effects on pDCs.