Complement Component Deficiencies Research Articles

Monogenic lupus with neuroregression in an infant due to rare compound heterozygous variants in C1QA gene: Case based review.

Monogenic lupus is a rare variant of systemic lupus erythematosus (SLE) that develops in patients with a single gene disorder. Early complement component deficiencies were the first forms of monogenic lupus to be described and C1Q gene mutations are one of the most common forms. C1QA complement deficiency has been reported to occur usually due to biallelic variants in C1QA gene and compound heterozygous variants in C1QA gene have rarely been reported. Majority of the monogenic lupus patients with C1Q deficiency present with mucocutaneous, renal, and musculoskeletal manifestations. Our patient is an unusual case of monogenic lupus with severe neurological manifestations along with cutaneous, haematological, and hepatic manifestations secondary to rare compound heterozygous variants in C1QA gene and anti-ribosomal P autoantibody positivity. She was treated with glucocorticoids, rituximab and fresh frozen plasma with partial neurological recovery. Thus, we present a unique case of monogenic lupus due to a rare compound heterozygous variant in C1QA gene with a brief review of literature.

Molecular aspects of hereditary complement component C5 deficiency in humans

IntroductionThe complement system plays a key role in the host defense against pathogens. The deficiency of complement components predisposes the system to recurrent infections and autoimmune diseases. In particular, serum C5 deficiency (C5D) may be serious for human health, because this protein plays a key role in controlling infections, mainly with <i>Neisseria</i> spp.AimThe aim of this article is to present the structure and function of the human C5 gene encoding complement component C5, with particular regard to the molecular characteristics of the mutations causing hereditary complement C5 deficiency.Material and methodsThis article is based on the available literature. A total of 35 articles were included in the study.Results and discussionBased on the literature review, it was shown that C5 mediates inflammatory processes and bacterial cytolysis. The cause of hereditary C5 deficiency in humans is inefficient or reduced serum C5 biosynthesis, due to mutations in the C5 gene. This quantitative and functional C5 deficiency is associated with recurrent <i>Neisseria</i> spp. infections, the lack of bactericidal activity and an impaired ability of serum to induce chemotaxis. The molecular characterization of previously described C5D-related mutations in the human C5 gene has been performed, and the clinical presentation of some molecularly examined C5D probands has also been discussed.ConclusionsThe deficiency of C5 protein, which bridges innate and adaptive immunity, is related with 18 different mutations in the C5 gene found in over 30 families of various origins. Screening for complement defects seems particularly important, especially in asymptomatic relatives of probands.

Expert Perspectives on the Vaccination of Individuals Who Are at Increased Risk of Meningococcal Disease Due to Medical Conditions: A Podcast.

Patients with functional or anatomic asplenia, including sickle cell anemia; complement component deficiency; or human immunodeficiency virus (HIV) infection have a significantly increased risk of developing meningococcal disease. The Advisory Committee on Immunization Practices (ACIP) of the Centers for Disease Control and Prevention (CDC) recommends vaccination with a quadrivalent meningococcal conjugate vaccine against serogroupsA, C, W, and Y (MenACWY) for individuals 2months of age or older who are diagnosed with functional or anatomic asplenia, complement component deficiency, or HIV infection. Vaccination with a meningococcal vaccine against serogroupB (MenB) is also recommended for individuals 10years of age or older who are diagnosed with functional or anatomic asplenia or complement component deficiency. Despite these recommendations, recent studies have shown that vaccination coverage in these populations is low. In this podcast, the authors discuss the challenges for implementing vaccine recommendations for individuals with medical conditions at increased risk of developing meningococcal disease and discuss strategies to increase coverage. Suboptimal vaccination rates could be addressed by better educating healthcare providers about recommendations for MenACWY and MenB vaccines in individuals at increased risk, increasing awareness of low vaccination coverage, and tailoring the education to the needs of particular healthcare providers and their respective patient populations. Barriers to vaccination could also be removed by administering vaccines at alternative sites of care, bundling preventative services, and implementing vaccination reminder systems that are tied to immunization information systems.

Streptococcus pneumoniae interactions with the complement system.

Host innate and adaptive immunity to infection with Streptococcus pneumoniae is critically dependent on the complement system, demonstrated by the high incidence of invasive S. pneumoniae infection in people with inherited deficiency of complement components. The complement system is activated by S. pneumoniae through multiple mechanisms. The classical complement pathway is activated by recognition of S. pneumoniae by C-reactive protein, serum amyloid P, C1q, SIGN-R1, or natural or acquired antibody. Some S. pneumoniae strains are also recognised by ficolins to activate the mannose binding lectin (MBL) activation pathway. Complement activation is then amplified by the alternative complement pathway, which can also be activated by S. pneumoniae directly. Complement activation results in covalent linkage of the opsonic complement factors C3b and iC3b to the S. pneumoniae surface which promote phagocytic clearance, along with complement-mediated immune adherence to erythrocytes, thereby protecting against septicaemia. The role of complement for mucosal immunity to S. pneumoniae is less clear. Given the major role of complement in controlling infection with S. pneumoniae, it is perhaps unsurprising that S. pneumoniae has evolved multiple mechanisms of complement evasion, including the capsule, multiple surface proteins, and the toxin pneumolysin. There is considerable variation between S. pneumoniae capsular serotypes and genotypes with regards to sensitivity to complement which correlates with ability to cause invasive infections. However, at present we only have a limited understanding of the main mechanisms causing variations in complement sensitivity between S. pneumoniae strains and to non-pathogenic streptococci.

Moyamoya Disease Associated with a Deficiency of Complement Component 6

ObjectivesComplement component 6 (C6) deficiency is a very rare genetic defect that leads to significantly diminished synthesis, secretion, or function of C6. In the current report, we demonstrate a previously undescribed, homozygous missense mutation in exon 17 of the C6 gene (c.2545A>G p.Arg849Gly) in a 35-year-old Japanese woman with moyamoya disease and extremely low levels of CH50 (<7.0 U/mL). Materials and MethodsThe complement gene analysis using hybridization capture-based next generation sequencing was performed. CH50 was determined in patient's plasma mixed with plasma from a healthy donor or purified human C6 protein. Western blot was performed on patient's plasma using polyclonal antibodies against C6, with healthy donor's plasma and purified human C6 protein as positive controls while C6-depleted human serum as a negative control. The carriage of ring finger protein 213 variant (c.14576G>A p.Arg4859Lys), a susceptibility gene for moyamoya disease, was examined by direct sequencing. ResultsCH50 mixing test clearly showed a deficiency pattern, being rescued by addition of only 1% healthy donor's plasma or 1 μg/mL purified human C6 protein (1/50-1/100 of physiological concentration). Western blot revealed the absence of C6 protein in the patient's plasma, confirming a quantitative deficiency of C6. The ring finger protein 213 variant was not detected. ConclusionsOur data implies that unrecognized complement deficiencies would be harbored in cerebrovascular diseases with unknown etiologies.

Emerging roles of the complement system in host-pathogen interactions.

The complement system has historically been entertained as a fluid-phase, hepatically derived system which protects the intravascular space from encapsulated bacteria. However, there has been an increasing appreciation for its role in protection against non-encapsulated pathogens. Specifically, we have an improved understanding of how pathogens are recognized by specific complement proteins, as well as how they trigger and evade them. Additionally, we have an improved understanding of locally derived complement proteins, many of which promote host defense. Moreover, intracellular complement proteins have been identified that facilitate local protection and barrier function despite pathogen invasion. Our review aims to summarize these advances in the field as well as provide an insight into the pathophysiological changes occurring when the system is dysregulated in infection.

Genetic workup as a complementary tool for the diagnosis of primary complement component deficiencies: a multicenter experience.

Awareness of risk factors for primary complement deficiencies, even at the first infectious episode, should facilitate prompt immune and genetic workup, commencing diagnosis and proper treatment for the patient and family. •Deficiencies in the classical terminal complement components increase susceptibility to invasive meningococcal infections. • Recurrent meningococcal infections mandate a diagnostic workup of the complement system. •Genetic workup can be utilized for prompt diagnosis of complement deficiencies. •High rates of consanguinity, even in the presence of a single meningococcal infection, should promote immune and genetic workups.

Low Meningococcal Vaccination Rates Among Patients With Newly Diagnosed Complement Component Deficiencies in the United States.

Meningococcal vaccination is recommended for patients with complement component deficiencies (CDs) in the United States. In this retrospective database study, only 4.6% and 2.2% of patients received MenACWY and MenB vaccination, respectively, within 3 years of CD diagnosis. Thus, meningococcal vaccination rates among patients with CDs need to be improved.

#92: What Is the Optimal Management of Patients Immunosuppressed with the Anti-compliment Monoclonal Antibody, Eculizumab? A Case Report and Review

Abstract Background Patients with deficiencies of terminal components of complement are at hundreds to thousands fold increased risk of severe and fatal Neisseria spp. infections compared with the general population. Eculizumab is a newly approved monoclonal antibody C5 complement inhibitor. It is indicated for the treatment of atypical hemolytic uremic syndrome (atypical HUS), myasthenia gravis, and paroxysmal nocturnal hemoglobinuria. Because of the complement-depleting effect of Eculizumab dosing (Soliris®, Alexion Pharmaceuticals, Munich, Germany), patients are immunosuppressed for specific infectious pathogens (including Neisseria species) against which protection partially relies on normal complement activity. Because Eculizumab treatment is associated with a dramatically increased risk of Neisseria species. infections, recommendations for Neisseria meningitidis vaccination and antibiotic prophylaxis are contained in Eculizumab prescribing information. However, the most appropriate prevention of infections after Eculizumab has yet to be determined. Methods Case report and literature review. Results A previously healthy 7-year-old male was diagnosed with atypical HUS which included renal failure progressing to dialysis, persistent thrombocytopenia, hemolytic anemia, and hemoglobinuria. Stool cultures and a stool multiplex PCR panel did not detect Shiga-like producing E. coli nor E. coli O157/H7. Eculizumab dosing was therefore planned and Infectious Diseases consultation was obtained for appropriate preventions. The FDA Prescribing Information recommends Neisseria meningitidis vaccination before starting Eculizumab or, if immediate Eculizumab is necessary, to use antibiotic prophylaxis until 2 weeks after vaccination. The accepted protective titer after meningococcal vaccination is population based and uses the serum bactericidal assay (SBA). An antibody titer of &amp;gt;1:4 (human compliment) or 1:8 (rabbit complement) is considered protective. However, this “gold standard” assay incorporates the use of exogenous human or rabbit complement. The protective SBA titers in subjects with terminal complement component deficiencies may not be properly assessed using these same SBA titer protective thresholds. Furthermore, serious meningococcal infections have occurred after appropriate vaccination in patients receiving chronic Eculizumab treatments (ie for paroxysmal nocturnal hemoglobinuria). Finally, SBA protective levels after single Neisseria meningitidis vaccination have not been achieved in majorities of patients with renal failure receiving dialysis and or transplant immunosuppression. Conclusions The current Eculizumab prescribing information recommendations for vaccination and antimicrobial prophylaxis may be inadequate to prevent serious Neisseria infections. Repeated Neisseria meningitidis vaccination and extended antibiotic prophylaxis may afford better protection in patients chronically dosed with Eculizumab.

Identification of a novel mutation in the C6 gene of a Han Chinese C6SD child with meningococcal disease.

Deficiency of the sixth complement component (C6D) is a genetic disease associated with increased susceptibility to Neisseria meningitides infection. Individuals with C6D usually present with recurrent meningococcal disease (MD). According to the patients' C6 levels, C6D is divided into complete genetic deficiency of C6 and subtotal deficiency of C6 (C6SD). The present study reported on a Han Chinese pediatric patient with MD, in whom further investigation revealed a C6SD genetic lesion. A heterozygote nonsense mutation (c.1062C>G/p.Y354*) in the C6 gene was identified by Sanger sequencing. The mutation alters the tyrosine codon at position 354 to a termination codon and results in a truncated protein. In conclusion, the genetic lesion of a pediatric patient with C6SD who was diagnosed due to having MD was investigated and a novel pathogenic mutation in the C6 gene was identified. The study confirmed the clinical diagnosis for this patient with C6SD and also expanded the spectrum of C6 mutations.

26. Factors Associated with Meningococcal Vaccination among Patients with Newly Diagnosed High-Risk Conditions

BackgroundVaccination is recommended for persons at increased risk for invasive meningococcal disease (IMD) due to complement component deficiency (CD), asplenia or human immunodeficiency virus (HIV) infection. However, uptake of quadrivalent conjugate and polysaccharide meningococcal vaccines (MenACWY) one year following a new high-risk diagnosis is very low (doi:10.1093/ofid/ofz360.2403). This retrospective cohort study identified factors associated with MenACWY vaccination among patients newly diagnosed with CD or HIV.MethodsPatients identified from a large US commercial administrative claims database (Optum Research Database) with continuous enrollment for ≥12 months before and ≥6 months after appearance of an incident high-risk diagnosis through the end of the study period (3/31/2018) were considered eligible (Figure). Cox proportional hazards regression models were used to identify characteristics associated with time to receipt of ≥1 dose of MenACWY during time periods corresponding with Advisory Committee on Immunization Practices (ACIP) recommendations.FigureStudy Design SchematicResultsThe CD cohort consisted of 1,470 (mean=40.9 years of age) patients and the HIV cohort of 1,208 (38.8 years). Only 7.9% and 20.8% of patients with CD or HIV, respectively, received ≥1 dose of MenACWY between their index date and the end of the study period. A strong association between receipt of MenACWY and pneumococcal vaccines was seen for CD [hazard ratio (HR): 3.2; 95% CI: 1.8–5.7] and HIV [23.0; 13.9–38.1]. Age (11–18 years; for CD only) and having a well-care visit after the index date (for CD and HIV) was associated with higher likelihood of vaccination. Vaccination rates for HIV were lowest in the South.ConclusionThe association of MenACWY vaccination with age in patients with CD suggests confusion between routine age-based and high-risk recommendations, whereas in patients with CD or HIV, the association with pneumococcal vaccines suggests that providers recognize the overlap in risk factors for IMD and pneumococcal disease. Ensuring healthcare access for these vulnerable patients and educating providers about high-risk recommendations is crucial.FundingGlaxoSmithKline Biologicals SA (study identifier: HO-18-19581)Disclosures Parinaz Ghaswalla, PhD, ORCID: 0000-0002-2883-5590, GlaxoSmithKline (Employee, Shareholder) Lindsay Bengtson, PhD, MPH, Optum (Employee, I am an employee of Optum. Optum was paid by GSK for this work. My employment at Optum is not contingent upon this work.) Gary S. Marshall, MD, GlaxoSmithKline (Consultant, Scientific Research Study Investigator)Merck (Consultant, Scientific Research Study Investigator)Pfizer (Consultant, Scientific Research Study Investigator)Sanofi Pasteur (Consultant, Grant/Research Support, Scientific Research Study Investigator, Honorarium for conference lecture)Seqirus (Consultant, Scientific Research Study Investigator) Ami R. Buikema, MPH, Optum (Employee, I am an employee of Optum. Optum was paid by GSK for this work. My employment at Optum is not contingent upon this work.) Tim Bancroft, PhD, Optum (Employee, I am an employee of Optum. Optum was paid by GSK for this work. My employment at Optum is not contingent upon this work.) Krista Schladweiler, PhD, Optum (Employee, I am an employee of Optum. Optum was paid by GSK for this work. My employment at Optum is not contingent upon this work.) Eleena Koep, MS, Optum (Employee) Patricia Novy, PhD, GSK (Employee, Shareholder) Cosmina Hogea, PhD, GlaxoSmithKline (Employee, Shareholder)

Deficiency of complement component 3 may be linked to the development of constipation in FVB/N‐C3em1Hlee/Korl mice

Alterations in complement component 3 (C3) expression has been reported to be linked to several bowel diseases including Crohn's disease, inflammatory bowel disease, and ulcerative colitis; however, the association with constipation has never been investigated. In this study, we aimed to investigate the correlation between C3 regulation and constipation development using a C3 deficiency model. To achieve these, alterations in stool excretion, transverse colon histological structure, and mucin secretion were analyzed in FVB/N-C3em1Hlee /Korl (C3 knockout, C3 KO) mice with the deletion of 11 nucleotides in exon 2 of the C3 gene. The stool excretion parameters, gastrointestinal transit, and intestine length were remarkably decreased in C3 KO mice compared with wild-type (WT) mice, although there was no specific change in feeding behavior. Furthermore, C3 KO mice showed a decrease in mucosal and muscle layer thickness, alterations in crypt structure, irregular distribution of goblet cells, and an increase of mucin droplets in the transverse colon. Mucin secretion was suppressed, and they accumulated in the crypts of C3 KO mice. In addition, the constipation phenotypes detected during C3 deficiency were confirmed in FVB/N mice treated with C3 convertase inhibitor (rosmarinic acid (RA)). Similar phenotypes were observed with respect to stool excretion parameters, gastrointestinal transit, intestine length, alterations in crypt structure, and mucin secretion in RA-treated FVB/N mice. Therefore, the results of the present study provide the first scientific evidence that C3 deficiency may play an important role in the development of constipation phenotypes in C3 KO mice.

Shared clinical decision making important for MenB vaccines

CDC's Advisory Committee on Immunization Practices (ACIP) has published its 2020 recommendations for meningococcal vaccination, which cover use of the three quadrivalent conjugate vaccines—meningococcal serotypes A, C, W, and Y (MenACWY)—and two available meningococcal serogroup B (MenB) vaccines. The recommendations call on shared clinical decision making for the MenB vaccine for adolescents and young adults ages 16 to 23 years and highlight the importance of these vaccines for patients at increased risk. Shared clinical decision making allows providers and patients an opportunity to discuss the risks of infection and the benefits of vaccination suitable to each individual's needs. For the MenB vaccines, ACIP recommends a shared clinical decision making approach for those ages 16 to 23 years, with considerations given to the serious nature of meningococcal infections; the increased risk among college students, especially first-year students attending a 4-year university; and the protection provided by the MenB vaccines against most strains of serogroup B Neisseria meningitidis. “Pharmacists are in a unique position to have a shared clinical decision conversation with patients about the risks of serogroup B meningococcal disease,” said Adam C. Welch, PharmD, MBA, FAPhA, associate professor of pharmacy practice at East Tennessee State University Bill Gatton College of Pharmacy. “Pharmacists can use the strong relationships they have with their patients to inform MenB shared clinical decision making. They’ll know if someone's son or daughter is joining a fraternity or sorority and therefore will be at higher risk.” Shared decision making in health care is not a new concept. The Agency for Healthcare Research and Quality (AHRQ) developed The SHARE Approach: Essential Steps of Shared Decisionmaking, which can be applied to vaccinations. This tool outlines five steps health professionals can take to ensure that they are using shared decision making effectively with patients during clinical encounters (see sidebar at right). If patients decide to receive the MenB vaccination series, clinicians should be aware that two vaccines are available: MenB-FHbp (Trumenba—Pfizer) and MenB-4C (Bexsero—GlaxoSmithKline). Each requires two doses to be given at different times. The MenB-FHbp is given at 0 and 6 months, and the MenB-4C is given as two doses at least 1 month apart or longer. The preferred age for vaccination is between 16 and 18 years, and it is important to note that the MenB-FHbp and MenB-4C are not interchangeable. ACIP also recommends the use of MenB vaccines for patients ages 10 years or older who are at increased risk for MenB disease. These patients include those who have persistent complement component deficiencies, those receiving a complement inhibitor, those who have anatomic or functional asplenia, microbiologists routinely exposed to isolates of N. meningitidis, and those at high risk because of an outbreak. Both MenB vaccines are FDA approved for use in patients ages 10 years to 25 years. The ACIP recommendations also cover the appropriate use of MenACWY vaccination, with routine vaccination recommended for adolescents at age 11 or 12 years and a booster at age 16. In addition, routine vaccination is recommended for patients ages 2 months or older who are at increased risk for meningococcal disease. Three quadrivalent meningococcal conjugate vaccines are FDA-approved: MenACWY-D (Menactra—SanofiPasteur), MenACWY-CRM (Menveo—GlaxoSmithKline), and MenACWY-TT (MenQuadfi—Sanofi Pasteur). The three MenACWY vaccines are interchangeable, but use of the same vaccine is recommended (not required) for all doses. The SHARE Approach: Essential Steps of Shared Decisionmaking▪Step 1: Seek your patient's participation.▪Step 2: Help your patient explore and compare treatment options.▪Step 3: Assess your patient's values and preferences.▪Step 4: Reach a decision with your patient.▪Step 5: Evaluate your patient's decision. The SHARE Approach: Essential Steps of Shared Decisionmaking ▪Step 1: Seek your patient's participation.▪Step 2: Help your patient explore and compare treatment options.▪Step 3: Assess your patient's values and preferences.▪Step 4: Reach a decision with your patient.▪Step 5: Evaluate your patient's decision. “It is important to maintain complete documentation, preferably in an immunization information system [like a registry], as many of the meningococcal vaccines have timing considerations with other vaccines such as DTaP and PCV13 [pneumococcal 13-valent conjugate vaccine],” said Welch. He also noted that special care should be taken in documenting which MenB vaccine was administered, as the two formulations are not interchangeable.

Meningococcal Vaccination: Recommendations of the Advisory Committee on Immunization Practices, United States, 2020.

SummaryThis report compiles and summarizes all recommendations from CDC’s Advisory Committee on Immunization Practices (ACIP) for use of meningococcal vaccines in the United States. As a comprehensive summary and update of previously published recommendations, it replaces all previously published reports and policy notes. This report also contains new recommendations for administration of booster doses of serogroup B meningococcal (MenB) vaccine for persons at increased risk for serogroup B meningococcal disease. These guidelines will be updated as needed on the basis of availability of new data or licensure of new meningococcal vaccines. ACIP recommends routine vaccination with a quadrivalent meningococcal conjugate vaccine (MenACWY) for adolescents aged 11 or 12 years, with a booster dose at age 16 years. ACIP also recommends routine vaccination with MenACWY for persons aged ≥2 months at increased risk for meningococcal disease caused by serogroups A, C, W, or Y, including persons who have persistent complement component deficiencies; persons receiving a complement inhibitor (e.g., eculizumab [Soliris] or ravulizumab [Ultomiris]); persons who have anatomic or functional asplenia; persons with human immunodeficiency virus infection; microbiologists routinely exposed to isolates of Neisseria meningitidis; persons identified to be at increased risk because of a meningococcal disease outbreak caused by serogroups A, C, W, or Y; persons who travel to or live in areas in which meningococcal disease is hyperendemic or epidemic; unvaccinated or incompletely vaccinated first-year college students living in residence halls; and military recruits. ACIP recommends MenACWY booster doses for previously vaccinated persons who become or remain at increased risk.In addition, ACIP recommends routine use of MenB vaccine series among persons aged ≥10 years who are at increased risk for serogroup B meningococcal disease, including persons who have persistent complement component deficiencies; persons receiving a complement inhibitor; persons who have anatomic or functional asplenia; microbiologists who are routinely exposed to isolates of N. meningitidis; and persons identified to be at increased risk because of a meningococcal disease outbreak caused by serogroup B. ACIP recommends MenB booster doses for previously vaccinated persons who become or remain at increased risk. In addition, ACIP recommends a MenB series for adolescents and young adults aged 16–23 years on the basis of shared clinical decision-making to provide short-term protection against disease caused by most strains of serogroup B N. meningitidis.

Complement Deficiencies Result in Surrogate Pathways of Complement Activation in Novel Polygenic Lupus-like Models of Kidney Injury.

Lupus nephritis (LN) is a major contributor to morbidity and mortality in lupus patients, but the mechanisms of kidney damage remain unclear. In this study, we introduce, to our knowledge, novel models of LN designed to resemble the polygenic nature of human lupus by embodying three key genetic alterations: the Sle1 interval leading to anti-chromatin autoantibodies; Mfge8-/- , leading to defective clearance of apoptotic cells; and either C1q-/- or C3-/- , leading to low complement levels. We report that proliferative glomerulonephritis arose only in the presence of all three abnormalities (i.e., in Sle1.Mfge8 -/- C1q -/- and Sle1.Mfge8 -/- C3 -/- triple-mutant [TM] strains [C1q -/-TM and C3-/- TM, respectively]), with structural kidney changes resembling those in LN patients. Unexpectedly, both TM strains had significant increases in autoantibody titers, Ag spread, and IgG deposition in the kidneys. Despite the early complement component deficiencies, we observed assembly of the pathogenic terminal complement membrane attack complex in both TM strains. In C1q-/- TM mice, colocalization of MASP-2 and C3 in both the glomeruli and tubules indicated that the lectin pathway likely contributed to complement activation and tissue injury in this strain. Interestingly, enhanced thrombin activation in C3-/- TM mice and reduction of kidney injury following attenuation of thrombin generation by argatroban in a serum-transfer nephrotoxic model identified thrombin as a surrogate pathway for complement activation in C3-deficient mice. These novel mouse models of human lupus inform the requirements for nephritis and provide targets for intervention.

2726. Meningococcal Vaccination Among Patients Newly Diagnosed at High-Risk for Meningococcal Disease in the United States

BackgroundQuadrivalent conjugate and polysaccharide meningococcal vaccines (MenACWY) have been recommended in the United States for patients at high-risk due to functional or anatomic asplenia, complement component deficiency (CD) and human immunodeficiency virus (HIV) infection. Serogroup B vaccines (MenB) are recommended for patients ≥10 years of age with asplenia or CD. Little is currently known about meningococcal vaccine uptake and time to vaccination among patients with incident high-risk diagnoses.MethodsPatients newly diagnosed (1 inpatient or ≥2 outpatient medical claims with evidence of the condition ≥30 days apart) with functional or anatomic asplenia (excluding sickle cell disease), CD or HIV infection were identified in the Optum Research Database. Continuous enrollment for ≥12 months before and ≥6 months after the diagnosis date (index date) was required. Patients with evidence of pre-existing conditions were excluded. MenACWY uptake was assessed among patients ≥2 years of age at index date from January 1, 2010 for asplenia and CD, and January 1, 2016 for HIV infection, through March 31, 2018; and MenB uptake among patients ≥10 years of age at index date from January 1, 2015 through March 31, 2018. Current Procedural Terminology and National Drug Codes on medical claims were used to capture vaccinations. For each condition, Kaplan–Meier analysis was used to estimate uptake and time to receipt of ≥1 dose of each vaccine for up to 5 years post-index date; vaccinations within 90 days before the index date were also included in calculations.ResultsAmong asplenia patients, the percentage with receipt of ≥1 dose of MenACWY at 1, 2.5, and 5 years post-index date was 6.6%, 9.4%, and 13.3%, respectively; for CD patients the corresponding percentages were 2.2%, 4.8%, and 8.3%; and for HIV patients at 1 and 2.5 years post-index date the percentages were 10.8% and 19.8% (Figure 1). Receipt of ≥1 dose of MenB at 1 and 2.5 years post-index date was 1.7% and 3.1%, respectively, for asplenia patients and 1.1% and 2.5%, respectively, for CD patients (Figure 2).ConclusionUptake of meningococcal vaccines in patients newly diagnosed with high-risk conditions is very low and the time to vaccination is long, leaving patients vulnerable to invasive meningococcal disease for extended periods of time. Disclosures All authors: No reported disclosures.

Complement, infection, and autoimmunity.

Complement system dysfunction in terms of upregulation, downregulation, or dysregulation can create an imbalance of both host defense and inflammatory response leading to autoimmunity. In this review, we aimed at describing the role of complement system in host defense to inflection and in autoimmunity starting from the evidence from primary and secondary complement system deficiencies. Complement system has a determinant role in defense against infections: deficiencies of complement components are associated with increased susceptibility to infections. Primary complement system deficiencies are rare disorders that predispose to both infections and autoimmune diseases. Secondary complement system deficiencies are the result of the complement system activation with consumption. Complement system role in enhancing risk of infective diseases in secondary deficiencies has been demonstrated in patients affected by systemic autoimmune disorders, mainly systemic lupus erythematosus and vasculitis. The relationship between the complement system and autoimmunity appears paradoxical as both the deficiency and the activation contribute to inducing autoimmune diseases. In these conditions, the presence of complement deposition in affected tissues, decreased levels of complement proteins, and high levels of complement activation fragments in the blood and vessels have been documented.

MHC Genomics and Disease: Looking Back to Go Forward.

Ancestral haplotypes are conserved but extremely polymorphic kilobase sequences, which have been faithfully inherited over at least hundreds of generations in spite of migration and admixture. They carry susceptibility and resistance to diverse diseases, including deficiencies of CYP21 hydroxylase (47.1) and complement components (18.1), as well as numerous autoimmune diseases (8.1). The haplotypes are detected by segregation within ethnic groups rather than by SNPs and GWAS. Susceptibility to some other diseases is carried by specific alleles shared by multiple ancestral haplotypes, e.g., ankylosing spondylitis and narcolepsy. The difference between these two types of association may explain the disappointment with many GWAS. Here we propose a pathway for combining the two different approaches. SNP typing is most useful after the conserved ancestral haplotypes have been defined by other methods.

Novel insights into the treatment of complement-mediated hemolytic anemias.

Complement-mediated hemolytic anemias can either be caused by deficiencies in regulatory complement components or by autoimmune pathogenesis that triggers inappropriate complement activation. In paroxysmal nocturnal hemoglobinuria (PNH) hemolysis is entirely complement-driven. Hemolysis is also thought to be complement-dependent in cold agglutinin disease (CAD) and in paroxysmal cold hemoglobinuria (PCH), whereas warm antibody autoimmune hemolytic anemia (wAIHA) is a partially complement-mediated disorder, depending on the subtype of wAIHA and the extent of complement activation. The pathophysiology, clinical presentation, and current therapies for these diseases are reviewed in this article. Novel, complement-directed therapies are being rapidly developed. Therapeutic terminal complement inhibition using eculizumab has revolutionized the therapy and prognosis in PNH but has proved less efficacious in CAD. Upstream complement modulation is currently being investigated and appears to be a highly promising therapy, and two such agents have entered phase II and III trials. Of these, the anti-C1s monoclonal antibody sutimlimab has shown favorable activity in CAD, while the anti-C3 cyclic peptide pegcetacoplan appears to be promising in PNH as well as CAD, and may also have a therapeutic potential in wAIHA.

Deficiency of early complement components protects against renal injury in a mouse model of brain death

Deficiency of early complement components protects against renal injury in a mouse model of brain death