BACKGROUND AND OBJECTIVES:A monogenic, age-related cerebral small vessel disease (cSVD), retinal vasculopathy with cerebral leukoencephalopathy and systemic manifestations (RVCL-S), causes accelerated vascular dementia, vision loss, and premature death. Given knowledge is limited regarding its pathophysiology, we examined the natural history of progression in imaging and cognitive endpoints to define the rate and variability of progression in a prospective RVCL-S cohort. We hypothesized that cerebral blood flow (CBF) and oxygen extraction fraction (OEF), as metrics of cerebral hypoxia-ischemia, would be associated with neurologic disease progression. METHODS:We performed sequential brain MRI and a cognitive battery in a prospective RVCL-S cohort. Arterial spin labeling and asymmetric spin echo quantified CBF and OEF in normal-appearing white matter (WM), respectively. Three neuroimaging endpoints of cSVD included the following: log-transformed, normalized fluid-attenuated inversion recovery WM hyperintensity (WMH) volume; WM microstructure using mean diffusivity; and normalized WM volume. Five cognitive and motor endpoints included Digit Symbol Substitution Test (DSST), category fluency, free recall, Montreal Cognitive Assessment (MoCA), and gait speed. Linear mixed-effects models examined age, CBF, and OEF in association with neuroimaging and cognitive progression. RESULTS:Twenty-five participants, aged 23-68 years (median 47 years, 56% female), underwent 151 scans over a median (25th, 75th) of 2.2 (1.8, 4.4) years. All neuroimaging and cognitive endpoints progressed over time, except for MoCA. Of neuroimaging endpoints, WMH volume demonstrated the largest rate of change (+31.3%/year, 95% CI 20.8%-42.3%). Of cognitive endpoints, DSST, a metric of processing speed, showed the steepest decline (-13.1 T-score points/decade, 95% CI -21.2 to -5.32), followed by free recall and category fluency (-5 [-7.9 to -2.4] and -4.1 [-7.2 to -1.2] T-score points per decade, respectively). The age at first brain lesion was estimated to be 30.6 (23.8, 35.8) years, modeled from individual WMH volume trajectories. In multivariable analysis, OEF, but not CBF, was independently associated with WMH growth (β = 3.73, 95% CI 0.63-6.83, p = 0.029) and change in WM microstructure (β = 0.175, 95% CI 0.029-0.32, p = 0.029). Neither OEF nor CBF was independently associated with cognitive decline. DISCUSSION:Elevated OEF in at-risk WM was associated with progression in WMH and impairment in WM microstructure, suggesting a role for tissue hypoxia-ischemia in underlying RVCL-S pathophysiology. Cerebral OEF holds promise as a predictive biomarker to risk-stratify patients with RVCL-S and other forms of cSVD.

The complement system is intimately engaged in systemic lupus erythematosus (SLE). Here we provide an account of how it is involved in the etiology, pathogenesis, diagnosis and management of human SLE. We have three primary objectives. One is to summarize the current status of employing complement measurement as a biomarker to facilitate clinical management. The second is to define how a genetic deficiency is causative. The third is to explain how the complement system mediates tissue damage in SLE. The field of complement research is entering an exciting renaissance with a wealth of new information on (1) genetic variants and their functional consequences in predisposing to disease and (2) availability of complement inhibitors to ameliorate tissue damage. Complement research has provided important breakthroughs relative to our understanding of the etiology and pathogenesis of SLE. Hopefully, therapeutic interventions aimed at modulating complement's role will have an even greater impact.

The complement system, a key component of the immune response, plays a dual role in cancer, influencing both tumor suppression and progression. Its three activation pathways (classical, alternative, and lectin) initiate immune processes, including opsonization and cell lysis. Within the tumor microenvironment, however, complement activation can paradoxically support immune-mediated tumor control or contribute to immune evasion and tumor growth. Therapeutic interventions such as radiation and certain chemotherapies can trigger complement activation by inducing immunogenic cell death and the release of damage-associated molecular patterns. This activation leads to the generation of anaphylatoxins C3a and C5a, which recruit immune cells to the tumor site and promote antitumor immunity. However, these same fragments may also foster an immunosuppressive microenvironment by attracting regulatory T cells and myeloid-derived suppressor cells, thereby limiting the efficacy of immunotherapies. Additionally, tumor cells often upregulate membrane complement regulatory proteins, including CD46, CD55, and CD59, to escape complement-mediated cytotoxicity and immune surveillance. Recent insights indicate that the complement system is a critical barrier to effective immunotherapy. Complement inhibition, particularly by targeting C3a receptor and C5a receptor 1, has been shown to synergize with immune checkpoint inhibitors (eg, anti-programmed cell death protein-1/programmed death-ligand 1), reversing complement-driven immunosuppression and enhancing T cell-mediated tumor rejection. Combining complement blockade with proimmunogenic therapies such as radiation or chemotherapy may further amplify these effects by uncoupling therapy-induced complement activation from its immunosuppressive consequences. Thus, the interplay between complement activation and cancer therapeutics presents a promising avenue for treatment innovations. Strategic modulation of complement, whether through genetic, pharmacologic, or antibody-based approaches, could sensitize tumors to immunotherapy and help overcome resistance mechanisms. Continued investigation into this crosstalk will be essential for designing effective combination strategies that maximize antitumor immunity while minimizing immune escape.

Background:Retinal vasculopathy with cerebral leukoencephalopathy and systemic manifestations (RVCL-S) is a rare small vessel disease marked by vision loss and neurocognitive deterioration. We sought to characterize the relatedness of the underlying retinal structure and cerebral disease. Methods:Participants with RVCL-S underwent optical coherence tomography (OCT) and brain MRI at baseline and 2 years. Total macular volume (TMV) and central subfield thickness (CST) were generated from OCT images. Neuroimaging metrics of ischemic brain injury included white matter hyperintensity (WMH) volume, white matter microstructure (mean diffusivity), and normalized white matter volume. Associations between retinal and neuroimaging metrics were assessed. Results:Eleven RVCL-S participants were included. Reduction in TMV was associated with reduced normalized white matter volume (β = 0.021, 95% CI [0.006, 0.036], p = 0.0137), increased WMH volume (β = -11.0, 95% CI [-17.4, -4.0], p = 0.0046), and a near-significant increase in mean diffusivity (β = -0.017, 95% CI [-0.035, -0.001], p = 0.057). CST was not associated with neuroimaging metrics. Percent change in TMV was associated with percent change in mean diffusivity (β = -0.61, 95% CI [-1.14, -0.084], p = 0.028). Conclusion:A metric of retinal structure, TMV, may provide a marker of cerebral disease severity in RVCL-S. Additional studies are needed to demonstrate whether early measures of TMV predict cerebral disease progression.

Initially identified as a regulator of complement activation on host cells, the known roles of CD46 (membrane cofactor protein [MCP]) have expanded. We now know that this ancient molecule is expressed on almost all nucleated cells as a family of four predominant isoforms. It also is involved in human reproduction, modulation of T cell activation and immunoinflammatory effector functions, autophagy, and the newly identified intracellular complement system (complosome). CD46 is also known as a "pathogen" magnet, being a port of entry for at least seven bacteria and five viruses. Moreover, CD46 has recently emerged as a key player in cancer biology. Numerous studies provide evidence of the association among elevated CD46 expression, malignant transformation, and metastasizing potential. These features, along with its roles as pathogen receptor, have made CD46 a target for cancer therapeutics. Thus, modified viral vectors (such as strains of adenovirus and measles virus) targeting CD46 currently are being exploited against a wide range of cancers. Another oncologic treatment utilizes a CD46-targeting human mAb as an antibody-drug conjugate. Herein, we review CD46 and its "multiverse" of cancer interactions.

Retinal vasculopathy with cerebral leukoencephalopathy and systemic manifestations (RVCL-S) is a rare autosomal dominant disease resulting from a frame-shift mutation in TREX1, an intracellular 3'-5' exonuclease 1. Hepatic findings include an elevated alkaline phosphatase (ALP) and nodular regenerative hyperplasia (NRH). Affected individuals typically succumb to brain lesions before clinically apparent hepatic manifestations; thus, little else is known about the hepatic pathology. Autopsy reports and a liver section from each (n = 11) of three unrelated kindreds with the most common mutation in TREX1 (V235Gfs∗6) were studied with standard and immunohistochemical stains. Cases were compared with "normal liver" controls from similar autopsy years. Cases consisted of six men and five women who died at a median age of 50 yr (range, 41-60 yr.). Seven had elevated ALP. Two had liver atrophy. Foci of NRH were variably detected in all. Inhomogeneous distribution of other findings included patternless parenchymal fibrous bands, approximation of vascular structures, and commonly, architectural changes of vascular structures. Only bile duct epithelia were unaffected. In addition, small trichrome-positive nodules were found along vein walls or isolated in the parenchyma. Rare foci of non-NRH hepatocytic nodules were noted in 3. Increased CD34 and altered α-SMA IHC expression were variably noted. Periportal ductules and perivenular K7 IHC expression were increased to unpredictable degrees. The extensive but inhomogeneous histopathologic findings in livers of autopsied patients with RVCL-S appear to involve hepatic vascular structures. These findings validate inclusion of vascular liver involvement beyond NRH in this complex hereditary disorder.

Background: A rare, monogenic cerebral small vessel disease (cSVD), retinal vasculopathy with cerebral leukoencephalopathy and systemic manifestations (RVCL-S), is associated with progressive cerebral ischemia and accelerated vascular cognitive impairment, resulting in premature death. We hypothesized that low cerebral blood flow (CBF) and elevated oxygen extraction fraction (OEF), as metrics of microvascular ischemia, would predict growth of white matter lesions (WML) and other neuroimaging manifestations of cSVD. Methods: We prospectively performed sequential brain MRI in a cohort of RVCL-S participants. Pseudocontinuous arterial spin labeling and asymmetric spin echo quantified CBF and OEF in normal appearing white matter (NAWM), respectively. WMLs were manually delineated on FLAIR. WM volumes were segmented and quantified. Diffusion tensor imaging (DTI) was used to measure NAWM mean diffusivity (MD). Results: Each of 14 RVCL-S participants underwent a median of 4.5 scans (IQR 3 - 6.75) with a median of 6.5 months (IQR 5.8 - 8.6) between scans performed over 2.9 years (IQR 2.0 - 4.2). Elevated NAWM OEF from the previous MRI, but not CBF, was associated with WML growth (ρ = 0.672, p < 0.0001), WM atrophy (ρ = 0.654, p < 0.0001), and increased MD (ρ = 0.714, p < 0.0001, Figure). After adjusting for age, sex, previous WML volume, and participant, previous OEF remained an independent predictor of WML growth (β = 7.04 (1.08, 13.01), p = 0.021). NAWM OEF was not retained in the mixed models predicting WM atrophy and MD. Conclusion: We found evidence that hypoxic-ischemic physiology, as measured by elevated OEF in NAWM, independently predicted WML growth. Previous OEF was associated with WM atrophy and decrease in microstructural integrity on follow-up. This work suggests that ischemia in normal brain regions may be a harbinger of disease progression in patients with RVCL-S, an inherited cSVD. Additionally, OEF may serve as a potential predictive biomarker in sporadic cSVD.

The complement system is a critical innate immune defense mechanism that also facilitates antigen recognition as well as antibody production through the adaptive immune response. Overall, complement activation contributes to the immune system's recognition and response to foreign pathogens and altered self. Regulating complement activation, particularly its powerful alternative pathway (AP) amplification loop, plays a key role in modulating tissue damage at sites of injury. Besides a predisposition to infections and autoimmunity (particularly systemic lupus erythematosus) in individuals deficient in activating components, variants in complement regulators are associated with multiple diseases including atypical hemolytic uremic syndrome (aHUS), paroxysmal nocturnal hemoglobinuria (PNH), and age -related macular degeneration (AMD). In particular, the pathogenesis of aHUS is commonly related to a rare heterozygous loss -of -function (LOF) mutation in the gene for complement factor H ( CFH ), CD46 [membrane cofactor protein ( MCP )] or factor I ( CFI ) or a gain -of -function (GOF) secondary to a variant in factor B ( CFB ) or C3 . The variants associated with complement regulators are the most prevalent and clearly demonstrate that cofactor activity (CA) is essential to control complement activation and thereby avoid collateral damage to normal tissues. Importantly, multiple studies have now established the therapeutic efficacy of blocking the membrane attack complex (MAC) with a humanized monoclonal antibody that targets the fifth component, C5. In this review, we primarily focus on insights derived from the assessment of rare variants in a membrane complement inhibitor CD46 in aHUS. We also discuss the putative pathological mechanisms relative to these variants of the complement system.

Primitive underpinnings of the alternative pathway (AP), namely, a C3-like protein, likely arose more than a billion years ago. The development of an AP amplification loop, while greatly enhancing speed and potency, also presents a double-edged sword. Although critical to combat an infectious disease, it is also potentially destructive, particularly in a chronic disease process involving vital organs where scarring and reduction of regulatory function can occur. Furthermore, new knowledge is pointing to genetic factors involved in an increasing number of complement-related diseases such as age-related macular degeneration. However, even a normal functioning repertoire of complement components can drive cellular damage as a result of low-level complement activation over time. Thus, the modern human AP now faces a new challenge: cumulatively-driven tissue damage from chronic inflammatory processes that mediate cellular injury. The impact of ongoing low-level AP-enhanced complement activation in disease processes is just beginning to be appreciated and studied. However, the sheer numbers of individuals affected by chronic diseases emphasize the need for novel therapeutic agents capable of modulating the AP. The more we learn about this ancient system, the greater is the likelihood of developing fresh perspectives that could contribute to improved human health.

Human adenovirus serotype 26 (Ad26) is used as a gene-based vaccine against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and HIV-1. However, its primary receptor portfolio remains controversial, potentially including sialic acid, coxsackie and adenovirus receptor (CAR), integrins, and CD46. We and others have shown that Ad26 can use CD46, but these observations were questioned on the basis of the inability to cocrystallize Ad26 fiber with CD46. Recent work demonstrated that Ad26 binds CD46 with its hexon protein rather than its fiber. We examined the functional consequences of Ad26 for infection in vitro and in vivo. Ectopic expression of human CD46 on Chinese hamster ovary cells increased Ad26 infection significantly. Deletion of the complement control protein domain CCP1 or CCP2 or the serine-threonine-proline (STP) region of CD46 reduced infection. Comparing wild-type and sialic acid-deficient CHO cells, we show that the usage of CD46 is independent of its sialylation status. Ad26 transduction was increased in CD46 transgenic mice after intramuscular (i.m.) injection but not after intranasal (i.n.) administration. Ad26 transduction was 10-fold lower than Ad5 transduction after intratumoral (i.t.) injection of CD46-expressing tumors. Ad26 transduction of liver was 1,000-fold lower than that ofAd5 after intravenous (i.v.) injection. These data demonstrate the use of CD46 by Ad26 in certain situations but also show that the receptor has little consequence by other routes of administration. Finally, i.v. injection of high doses of Ad26 into CD46 mice induced release of liver enzymes into the bloodstream and reduced white blood cell counts but did not induce thrombocytopenia. This suggests that Ad26 virions do not induce direct clotting side effects seen during coronavirus disease 2019 (COVID-19) vaccination with this serotype of adenovirus. IMPORTANCE The human species D Ad26 is being investigated as a low-seroprevalence vector for oncolytic virotherapy and gene-based vaccination against HIV-1 and SARS-CoV-2. However, there is debate in the literature about its tropism and receptor utilization, which directly influence its efficiency for certain applications. This work was aimed at determining which receptor(s) this virus uses for infection and its role in virus biology, vaccine efficacy, and, importantly, vaccine safety.

Retinal vasculopathy with cerebral leukoencephalopathy and systemic manifestations (RVCL-S) is a rare fatal autosomal dominant vasculopathy associated with mutations in the TREX1 gene. Only one de novo case has been reported in the literature. We report the long-term clinical, radiological, and pathological presentation of a patient with a de novo and novel mutation in this gene. Description of the clinical, genetic, imaging and pathologic characteristics is important to better characterize RVCL-S and prevent unnecessary interventions. RVCL-S should be considered in patients with tumefactive brain lesions unresponsive to immunotherapy.

Membrane cofactor protein (MCP; CD46), a ubiquitously expressed complement regulatory protein, serves as a cofactor for serine protease factor I to cleave and inactivate C3b and C4b deposited on host cells. However, CD46 also plays roles in human reproduction, autophagy, modulating T cell activation and effector functions and is a member of the newly identified intracellular complement system (complosome). CD46 also is a receptor for 11 pathogens ('pathogen magnet'). While CD46 deficiencies contribute to inflammatory disorders, its overexpression in cancers and role as a receptor for some adenoviruses has led to its targeting by oncolytic agents and adenoviral-based therapeutic vectors, including coronavirus disease of 2019 (COVID-19) vaccines. This review focuses on recent advances in identifying disease-causing CD46 variants and its pathogen connections.

Dengue is a mosquito-borne viral disease causing significant health and economic burdens globally. The dengue virus (DENV) comprises four serotypes (DENV1-4). Usually, the primary infection is asymptomatic or causes mild dengue fever (DF), while secondary infections with a different serotype increase the risk of severe dengue disease (dengue hemorrhagic fever, DHF). Complement system activation induces inflammation and tissue injury, contributing to disease pathogenesis. However, in asymptomatic or primary infections, protective immunity largely results from the complement system's lectin pathway (LP), which is activated through foreign glycan recognition. Differences in N-glycans displayed on the DENV envelope membrane influence the lectin pattern recognition receptor (PRR) binding efficiency. The important PRR, mannan binding lectin (MBL), mediates DENV neutralization through (1) a complement activation-independent mechanism via direct MBL glycan recognition, thereby inhibiting DENV attachment to host target cells, or (2) a complement activation-dependent mechanism following the attachment of complement opsonins C3b and C4b to virion surfaces. The serum concentrations of lectin PRRs and their polymorphisms influence these LP activities. Conversely, to escape the LP attack and enhance the infectivity, DENV utilizes the secreted form of nonstructural protein 1 (sNS1) to counteract the MBL effects, thereby increasing viral survival and dissemination.

Objective To characterize lesion evolution and neurodegeneration in retinal vasculopathy with cerebral leukoencephalopathy and systemic manifestations (RVCL-S) using multimodal MRI. Methods We prospectively performed MRI and cognitive testing in RVCL-S and healthy control cohorts. Gray and white matter volume and disruption of white matter microstructure were quantified. Asymmetric spin echo acquisition permitted voxel-wise oxygen extraction fraction (OEF) calculation as an in vivo marker of microvascular ischemia. The RVCL-S cohort was included in a longitudinal analysis of lesion subtypes in which hyperintense lesions on fluid-attenuated inversion recovery (FLAIR), T1-postgadolinium, and diffusion-weighted imaging were delineated and quantified volumetrically. Results Twenty individuals with RVCL-S and 26 controls were enrolled. White matter volume and microstructure declined faster in those with RVCL-S compared to controls. White matter atrophy in RVCL-S was highly linear (rho = -0.908, p < 0.0001). Normalized OEF was elevated in RVCL-S and increased with disease duration. Multiple cognitive domains, specifically those measuring working memory and processing speed, were impaired in RVCL-S. Lesion volumes, regardless of subtype, progressed/regressed with high variability as a function of age, while FLAIR lesion burden increased near time to death (p < 0.001). Conclusion RVCL-S is a monogenic microvasculopathy affecting predominantly the white matter with regard to atrophy and cognitive impairment. White matter volumes in RVCL-S declined linearly, providing a potential metric against which to test the efficacy of future therapies. Progressive elevation of white matter OEF suggests that microvascular ischemia may underlie neurodegeneration in RVCL-S.

Objective To characterize lesion evolution and neurodegeneration in retinal vasculopathy with cerebral leukoencephalopathy and systemic manifestations (RVCL-S) using multimodal MRI. Methods We prospectively performed MRI and cognitive testing in RVCL-S and healthy control cohorts. Gray and white matter volume and disruption of white matter microstructure were quantified. Asymmetric spin echo acquisition permitted voxel-wise oxygen extraction fraction (OEF) calculation as an in vivo marker of microvascular ischemia. The RVCL-S cohort was included in a longitudinal analysis of lesion subtypes in which hyperintense lesions on fluid-attenuated inversion recovery (FLAIR), T1-postgadolinium, and diffusion-weighted imaging were delineated and quantified volumetrically. Results Twenty individuals with RVCL-S and 26 controls were enrolled. White matter volume and microstructure declined faster in those with RVCL–S compared to controls. White matter atrophy in RVCL-S was highly linear (ρ = −0.908, p < 0.0001). Normalized OEF was elevated in RVCL-S and increased with disease duration. Multiple cognitive domains, specifically those measuring working memory and processing speed, were impaired in RVCL-S. Lesion volumes, regardless of subtype, progressed/regressed with high variability as a function of age, while FLAIR lesion burden increased near time to death (p < 0.001). Conclusion RVCL-S is a monogenic microvasculopathy affecting predominantly the white matter with regard to atrophy and cognitive impairment. White matter volumes in RVCL-S declined linearly, providing a potential metric against which to test the efficacy of future therapies. Progressive elevation of white matter OEF suggests that microvascular ischemia may underlie neurodegeneration in RVCL-S.

One of the most challenging aspects of cancer therapeutics is target selection. Recently, CD46 (membrane cofactor protein; MCP) has emerged as a key player in both malignant transformation as well as in cancer treatments. Normally a regulator of complement activation, CD46 is co-expressed as four predominant isoforms on almost all cell types. CD46 is highly overexpressed on a variety of human tumor cells. Clinical and experimental data support an association between increased CD46 expression and malignant transformation and metastasizing potential. Further, CD46 is a newly discovered driver of metabolic processes and plays a role in the intracellular complement system (complosome). CD46 is also known as a pathogen magnet due to its role as a receptor for numerous microbes, including several species of measles virus and adenoviruses. Strains of these two viruses have been exploited as vectors for the therapeutic development of oncolytic agents targeting CD46. In addition, monoclonal antibody-drug conjugates against CD46 also are being clinically evaluated. As a result, there are multiple early-phase clinical trials targeting CD46 to treat a variety of cancers. Here, we review CD46 relative to these oncologic connections.

Coronavirus disease 2019 (COVID-19), the disease caused by severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) has resulted in a global pandemic and a disruptive health crisis. COVID-19-related morbidity and mortality have been attributed to an exaggerated immune response. The role of complement activation and its contribution to illness severity is being increasingly recognized. Here, we summarize current knowledge about the interaction of coronaviruses with the complement system. We posit that (a) coronaviruses activate multiple complement pathways; (h) severe COVID-19 clinical features often resemble complementopathies; (c) the combined effects of complement activation, dysregulated neutrophilia, endothelial injury, and hypercoagulability appear to be intertwined to drive the severe features of COVID-19; (d) a subset of patients with COVID-19 may have a genetic predisposition associated with complement dysregulation; and (e) these observations create a basis for clinical trials of complement inhibitors in life-threatening illness.

Background Complement activation is a central pathophysiologic event in several autoimmune diseases. A key activation event is the conversion of native C3 to C3(H2O), where a highly reactive thioester bond in C3 is hydrolyzed. C3(H2O) can be utilized to generate C3 convertase, which further drives complement activation via the alternative pathway. C3(H2O) has been elusive to measure, but we have recently developed a novel ELISA-based assay allowing for its accurate measurement. We hypothesized that in autoimmune diseases where complement activation is a central feature, C3(H2O) levels will be elevated reflecting a primed state for triggering inappropriate alternative pathway activation and amplification. Methods Healthy adult subjects (n=5) and adults with classified SLE (n=6) were enrolled and consented for serum collection at Washington University School of Medicine. Frozen serum was tested either immediately after thawing or after incubation at room temperature or 37°C for 6 or 24 hours. C3(H2O) was measured by an ELISA assay that utilizes a capture antibody to C3b and a detection antibody to C3a. Data was analyzed using Prism version 7.0d (GraphPad Software, Inc.). Statistical significance was determined using 2-way ANOVA with Dunns multiple comparisons test. Results Substantial elevation of serum C3(H2O) levels were observed from patients with SLE following incubation at RT and 37°C compared to healthy controls. The differences were most pronounced in samples incubated at 37°C for 6 hours, with over a 4-fold increase in C3(H2O) levels in both the SLE samples. Interestingly, sera from both groups (healthy controls and SLE) did not reflect any difference in baseline C3(H2O) levels. Conclusions Both SLE and RA are associated with elevated C3(H2O) levels following in vitro incubation compared to healthy controls. These data suggest that the potential for C3(H2O) formation in SLE and RA patients are higher compared to healthy controls, which could support additional complement activation or utilization of C3(H2O) in other pathways such as intracellular activation in immune cells. Thus, In addition to a possible diagnostic tool for pathogenic autoimmunity, these data may also suggest novel mechanisms of how complement could drive symptomatic autoimmune disease. Funding Source(s): NIH R01 GM0099111