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"Carroll, Michael C"
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Overexpression of schizophrenia susceptibility factor human complement C4A promotes excessive synaptic loss and behavioral changes in mice
The complement component 4 (
C4
) gene is linked to schizophrenia and synaptic refinement. In humans, greater expression of
C4A
in the brain is associated with an increased risk of schizophrenia. To investigate this genetic finding and address how
C4A
shapes brain circuits in vivo, here, we generated a mouse model with primate-lineage-specific isoforms of
C4
, human
C4A
and/or
C4B
. Human C4A bound synapses more efficiently than C4B.
C4A
(but not
C4B
) rescued the visual system synaptic refinement deficits of
C4
knockout mice. Intriguingly, mice without C4 had normal numbers of cortical synapses, which suggests that complement is not required for normal developmental synaptic pruning. However, overexpressing
C4A
in mice reduced cortical synapse density, increased microglial engulfment of synapses and altered mouse behavior. These results suggest that increased C4A-mediated synaptic elimination results in abnormal brain circuits and behavior. Understanding pathological overpruning mechanisms has important therapeutic implications in disease conditions such as schizophrenia.
Overexpression of complement
C4A
is associated with schizophrenia risk. Using a novel mouse model, Yilmaz et al. find that increased expression of
C4A
leads to abnormal synaptic pruning and behavior, suggesting its importance as a therapeutic target.
Journal Article
Schizophrenia risk from complex variation of complement component 4
Schizophrenia is a heritable brain illness with unknown pathogenic mechanisms. Schizophrenia’s strongest genetic association at a population level involves variation in the major histocompatibility complex (MHC) locus, but the genes and molecular mechanisms accounting for this have been challenging to identify. Here we show that this association arises in part from many structurally diverse alleles of the complement component 4 (
C4
) genes. We found that these alleles generated widely varying levels of
C4A
and
C4B
expression in the brain, with each common
C4
allele associating with schizophrenia in proportion to its tendency to generate greater expression of
C4A
. Human C4 protein localized to neuronal synapses, dendrites, axons, and cell bodies. In mice, C4 mediated synapse elimination during postnatal development. These results implicate excessive complement activity in the development of schizophrenia and may help explain the reduced numbers of synapses in the brains of individuals with schizophrenia.
WebSchizophrenia is associated with genetic variation at the major histocompatibility complex locus; this study reveals that alleles at this locus associate with schizophrenia in proportion to their tendency to generate greater expression of complement component 4 (
C4A
) genes and that C4 promotes the elimination of synpases.
The genetics of schizophrenia
The strongest genetic association found in schizophrenia is its association to genetic markers across the major histocompatibility complex (MHC) locus, first described in three
Nature
papers in 2009. The association signal at the MHC is extremely complex. Here Steven McCarroll and colleagues report a dissection of the MHC association to schizophrenia. They find a strong contribution from many structurally diverse alleles of the complement component 4 (
C4
) genes. The linkage was higher for
C4
alleles that promoted greater expression of
C4A
, measured in the brain tissues of adult post-mortem donors with or without schizophrenia. The authors suggest that C4 may work with other components of the classical complement cascade to promote synaptic pruning, and demonstrate that C4 mediates synaptic refinement in a mouse model.
Journal Article
Lymph node metastases can invade local blood vessels, exit the node, and colonize distant organs in mice
Metastatic tumor cells are thought to reach distant organs by traveling through the blood circulation or the lymphatic system. Two studies of mouse models now suggest a hybrid route for tumor cell dissemination. Pereira et al. and Brown et al. used distinct methodologies to monitor the fate of tumor cells in lymph nodes. They found that tumor cells could invade local blood vessels within a node, exit the node by entering the blood circulation, then go on to colonize the lung. Whether this dissemination route occurs in cancer patients is unknown; the answer could potentially change the way that affected lymph nodes are treated in cancer. Science , this issue p. 1403 , p. 1408 In mice, tumor cells can metastasize to distant organs by entering blood vessels within the local lymph node. Lymph node metastases in cancer patients are associated with tumor aggressiveness, poorer prognoses, and the recommendation for systemic therapy. Whether cancer cells in lymph nodes can seed distant metastases has been a subject of considerable debate. We studied mice implanted with cancer cells (mammary carcinoma, squamous cell carcinoma, or melanoma) expressing the photoconvertible protein Dendra2. This technology allowed us to selectively photoconvert metastatic cells in the lymph node and trace their fate. We found that a fraction of these cells invaded lymph node blood vessels, entered the blood circulation, and colonized the lung. Thus, in mouse models, lymph node metastases can be a source of cancer cells for distant metastases. Whether this mode of dissemination occurs in cancer patients remains to be determined.
Journal Article
The CLEC-2–podoplanin axis controls the contractility of fibroblastic reticular cells and lymph node microarchitecture
Lymph nodes expand after an inflammatory challenge to accommodate their increased cellularity. Turley and colleagues show that fibroblastic reticular cells regulate this expansion process through the interaction of podoplanin with its receptor CLEC-2 expressed on incoming dendritic cells.
In lymph nodes, fibroblastic reticular cells (FRCs) form a collagen-based reticular network that supports migratory dendritic cells (DCs) and T cells and transports lymph. A hallmark of FRCs is their propensity to contract collagen, yet this function is poorly understood. Here we demonstrate that podoplanin (PDPN) regulates actomyosin contractility in FRCs. Under resting conditions, when FRCs are unlikely to encounter mature DCs expressing the PDPN receptor CLEC-2, PDPN endowed FRCs with contractile function and exerted tension within the reticulum. Upon inflammation, CLEC-2 on mature DCs potently attenuated PDPN-mediated contractility, which resulted in FRC relaxation and reduced tissue stiffness. Disrupting PDPN function altered the homeostasis and spacing of FRCs and T cells, which resulted in an expanded reticular network and enhanced immunity.
Journal Article
Landscape of B cell immunity and related immune evasion in human cancers
Tumor-infiltrating B cells are an important component in the microenvironment but have unclear anti-tumor effects. We enhanced our previous computational algorithm TRUST to extract the B cell immunoglobulin hypervariable regions from bulk tumor RNA-sequencing data. TRUST assembled more than 30 million complementarity-determining region 3 sequences of the B cell heavy chain (IgH) from The Cancer Genome Atlas. Widespread B cell clonal expansions and immunoglobulin subclass switch events were observed in diverse human cancers. Prevalent somatic copy number alterations in the
MICA
and
MICB
genes related to antibody-dependent cell-mediated cytotoxicity were identified in tumors with elevated B cell activity. The IgG3–1 subclass switch interacts with B cell–receptor affinity maturation and defects in the antibody-dependent cell-mediated cytotoxicity pathway. Comprehensive pancancer analyses of tumor-infiltrating B cell–receptor repertoires identified novel tumor immune evasion mechanisms through genetic alterations. The IgH sequences identified here are potentially useful resources for future development of immunotherapies.
This comprehensive pancancer analysis of RNA-sequencing data from bulk tumors defines the landscape of tumor-infiltrating B cell–receptor repertoires and highlights new mechanisms of tumor immune evasion through genetic alterations.
Journal Article
B cell homeostasis and follicle confines are governed by fibroblastic reticular cells
Naive B and T cells exist in discrete zones in lymph nodes. Turley and colleagues demonstrate that a distinct subset of fibroblastic reticular cells reside in B cell zones, where they sustain B cell survival by providing BAFF.
Fibroblastic reticular cells (FRCs) are known to inhabit T cell–rich areas of lymphoid organs, where they function to facilitate interactions between T cells and dendritic cells. However,
in vivo
manipulation of FRCs has been limited by a dearth of genetic tools that target this lineage. Here, using a mouse model to conditionally ablate FRCs, we demonstrated their indispensable role in antiviral T cell responses. Unexpectedly, loss of FRCs also attenuated humoral immunity due to impaired B cell viability and follicular organization. Follicle-resident FRCs established a favorable niche for B lymphocytes via production of the cytokine BAFF. Thus, our study indicates that adaptive immunity requires an intact FRC network and identifies a subset of FRCs that control B cell homeostasis and follicle identity.
Journal Article
Mechanosensing by Peyer’s patch stroma regulates lymphocyte migration and mucosal antibody responses
Fibroblastic reticular cells (FRCs) and their specialized collagen fibers termed ‘conduits’ form fundamental structural units supporting lymphoid tissues. In lymph nodes, conduits are known to transport interstitial fluid and small molecules from afferent lymphatics into the nodal parenchyma. However, the immunological contributions of conduit function have remained elusive. Here, we report that intestinal Peyer’s patches (PPs) contain a specialized conduit system that directs the flow of water absorbed across the intestinal epithelium. Notably, PP FRCs responded to conduit fluid flow via the mechanosensitive ion channel Piezo1. Disruption of fluid flow or genetic deficiency of
Piezo1
on CCL19-expressing stroma led to profound structural alterations in perivascular FRCs and associated high endothelial venules. This in turn impaired lymphocyte entry into PPs and initiation of mucosal antibody responses. These results identify a critical role for conduit-mediated fluid flow in the maintenance of PP homeostasis and mucosal immunity.
Peyer’s patches (PPs) are sites of antibody production in the gut mucosa. Carroll and colleagues show the mechanosensory channel protein Piezo1 is required for the homeostatic maintenance of PPs. Specific loss of Piezo1 in FRCs disrupt PP structure and function, resulting in reduction of fecal IgA production and gut immunity.
Journal Article
Targeting C1q prevents microglia-mediated synaptic removal in neuropathic pain
Activation of spinal microglia following peripheral nerve injury is a central component of neuropathic pain pathology. While the contributions of microglia-mediated immune and neurotrophic signalling have been well-characterized, the phagocytic and synaptic pruning roles of microglia in neuropathic pain remain less understood. Here, we show that peripheral nerve injury induces microglial engulfment of dorsal horn synapses, leading to a preferential loss of inhibitory synapses and a shift in the balance between inhibitory and excitatory synapse density. This synapse removal is dependent on the microglial complement-mediated synapse pruning pathway, as mice deficient in complement C3 and C4 do not exhibit synapse elimination. Furthermore, pharmacological inhibition of the complement protein C1q prevents dorsal horn inhibitory synapse loss and attenuates neuropathic pain. Therefore, these results demonstrate that the complement pathway promotes persistent pain hypersensitivity via microglia-mediated engulfment of dorsal horn synapses in the spinal cord, revealing C1q as a therapeutic target in neuropathic pain.
Nerve injury activates microglia to remove spinal synapses, disrupting spinal sensory processing and contributing to chronic pain. Blocking complement protein C1q preserves synapses, highlighting a potential therapeutic target for neuropathic pain.
Journal Article
Autoreactivity profiles of influenza hemagglutinin broadly neutralizing antibodies
Epitope-focused approaches for selective clonal induction of broadly neutralizing antibodies (bnAbs) inform most current vaccine strategies for influenza virus and other rapidly evolving pathogens. The two conserved epitopes on the influenza hemagglutinin (HA) - the “stem” and the receptor-binding site (RBS) on the “head” - are the focus of the current “universal” influenza vaccine development efforts. Because stem-directed serum bnAbs are much less abundant than head-directed ones, we hypothesized that the HA stem bnAbs may be autoreactive and thus eliminated through the mechanisms of self-tolerance. We compared autoreactivity profiles of a set of stem and head-directed bnAbs. Most of the stem bnAbs we examined bound autoantigens; several showed staining of HEp-2 cells. A smaller proportion of the head-directed bnAbs were polyreactive. Gene usage did not correlate with autoreactivity. We suggest that complex foreign antigens may often have surface patches resembling some host epitope; our results indicate that HA stem epitopes resemble a host epitope more frequently than does the RBS.
Journal Article