new 4 WS_ primary immunodeficiencies I_ complement deficiencies.pdf

1/30/24, 11:03 AM Week 3: Fusion Session | Workshop: Primary Immunodeficiencies I: Complement Deficiencies: Hemtlgy Onclgy Infectn Imm - January 2024 A C3 deficiency will affect which complement activation pathways? (Choose the best answer)  None of the pathways  Classical pathway  Lectin pathway ...

1/30/24, 11:03 AM Week 3: Fusion Session | Workshop: Primary Immunodeficiencies I: Complement Deficiencies: Hemtlgy Onclgy Infectn Imm - January 2024 A C3 deficiency will affect which complement activation pathways? (Choose the best answer)  None of the pathways  Classical pathway  Lectin pathway  Alternative pathway  All three pathways  Check  1. A C3 deficiency will affect which complement activation pathways? (Choose the best answer) Alternative pathway Classical pathway Lectin pathway All three pathways (answer) None of the pathways 2. A properdin deficiency will affect which complement activation pathways? Alternative pathway (answer) Classical pathway Lectin pathway All three pathways None of the pathways 3. A C1 esterase inhibitor (C1 INH) deficiency will affect which of the following pathways? (Choose the best answer) Alternative pathway Classical pathway (answer) Coagulation pathway (answer) Kallikrein-kinin pathway (answer) Lectin pathway (answer) https://rossmed.instructure.com/courses/3318/pages/week-3-fusion-session-%7C-workshop-primary-immunodeficiencies-i-complement-deficiencies 5/8 1/30/24, 11:03 AM Week 3: Fusion Session | Workshop: Primary Immunodeficiencies I: Complement Deficiencies: Hemtlgy Onclgy Infectn Imm - January 2024 4. Recurrent infections with Gram-negative bacteria such as Neisseria meningitidis or N. gonorrhoeae would be indicative of a deficiency in which of the following complement components? C1 C4 C8 (answer) Mannose-binding lectin (MBL) MASP-1/MASP-2 5. A deficiency in which of the following complement components is most likely to decrease immune complex clearance? C3 (answer) C5 C8 C9 Properdin 6. A 15-year-old female adolescent presents to the ED with a 24-hour history of occipital headache, stiff neck, and vomiting. Physical examination reveals the following: pyrexia (38.5°C), heart rate of 120 bpm, respiratory rate of 18 bpm, blood pressure of 115/75 mmHg, stiffness in the neck with a positive Kernig's sign, and altered mental status. A CSF analysis performed is significant for the following: elevated opening pressure (250 mm H2O; RR: 80-200), 2,500 leukocytes/µL (RR: 0-5) with predominance of PMNs (95%), 25 mg/dL glucose (RR: 40-70), 500 mg/dL protein (RR: 20-50), and Gram-negative diplococci (free and within PMNs). A diagnosis of meningitis is reached (later confirmed by culture to be due to Neisseria meningitidis), and the patient is treated with ceftriaxone (IV). This patient has had similar infections in the past so further investigations are undertaken. Further laboratory data show that leukocyte numbers and functions are normal, but both CH50 and AH50 return abnormal results. What complement component is most likely to be deficient in this patient? C1 C4 C5 (answer) Mannose-binding lectin (MBL) Properdin 7. A 15-year-old male adolescent presents to the ED with a 24-hour history of occipital headache, stiff neck, and vomiting. Physical examination reveals the following: pyrexia (38.5°C), heart rate of 120 bpm, respiratory rate of 18 bpm, blood pressure of 115/75 mmHg, stiffness in the neck with a positive Kernig's sign, and altered mental status. A CSF analysis performed is significant for the following: elevated opening pressure (250 mm H2O; RR: 80-200), 2,500 leukocytes/µL (RR: 0-5) with predominance of PMNs (95%), 25 mg/dL glucose (RR: 40-70), 500 mg/dL protein (RR: 20-50), and Gram-negative diplococci (free and within PMNs). A diagnosis of meningitis is reached (later confirmed by culture to be due to Neisseria meningitidis), and the patient is treated with ceftriaxone (IV). This patient has had similar infections in the past so https://rossmed.instructure.com/courses/3318/pages/week-3-fusion-session-%7C-workshop-primary-immunodeficiencies-i-complement-deficiencies 6/8 1/30/24, 11:03 AM Week 3: Fusion Session | Workshop: Primary Immunodeficiencies I: Complement Deficiencies: Hemtlgy Onclgy Infectn Imm - January 2024 further investigations are undertaken. Further laboratory data show that leukocyte numbers and functions are normal, but the CH50 returns a normal result, whereas the AH50 returns an abnormal result. What complement component is most likely to be deficient in this patient? C1 C4 C5 Mannose-binding lectin (MBL) Properdin (answer) 8. A 14-year-old adolescent presents with recurrent pyogenic infections. Upon further investigation, laboratory tests show that leukocyte numbers and functions are normal, but that the CH50 returns abnormal results whereas the AH50 returns normal results. What complement component is most likely to be deficient in this patient? C2 (answer) C3 C5 C9 Properdin 9. A 35-year-old man presents with fatigue, dyspnea, abdominal pain, and hemoglobinuria. Physical examination reveals pallor, tachycardia, and tachypnea. Flow cytometry results show decreased glycosylphosphatidylinositol (GPI)-anchored proteins on blood cells. A diagnosis of paroxysmal nocturnal hemoglobinuria is made. A deficiency in which complement component is most likely in this individual? C1 C1 INH C2 CD59 (answer) Factor B 10. An 11-month-old infant presents with a history of recurrent bacterial and fungal infections, primarily affecting the skin and mucosa, as well as delayed separation of the umbilical cord. Absence of pus formation despite bacterial/fungal infections is noted and further laboratory investigations show leukocytosis with absence of leukocyte mobilization into the affected areas (i.e., biopsy of affected areas show an absence of neutrophils despite the neutrophilia). What complement component is most likely deficient in this patient? C4 CR1 CR2 CR3 (answer) CD55 https://rossmed.instructure.com/courses/3318/pages/week-3-fusion-session-%7C-workshop-primary-immunodeficiencies-i-complement-deficiencies 7/8 1/30/24, 11:16 AM Inherited disorders of the complement system - UpToDate GRAPHICS Complement pathways There are three major independent yet overlapping pathways for complement activation. In the classical pathway, immune complexes (Ag-Ab complexes) bind C1 via its C1q subcomponent, while its C1s protease subunit cleaves C4 and C2. The large C4b fragment binds to a target and subsequently captures the large fragment of C2 (C2b). This bimolecular complex forms an enzyme (the C3 convertase, C4bC2b) that cleaves C3 to C3b and releases the anaphylatoxin, C3a. The binding of C3b to the convertase (C4bC2bC3b) generates the C5 convertase. The lectin pathway is an analogous system, except that the initiating step is the binding by lectins to repetitive sugars on microbial surfaces. Mannose-associated serine proteases (MASPs) take the place of the C1 proteases. The alternative pathway (AP) continuously self-activates at a low level (a process called C3 tickover) to generate C3b that deposits on pathogens or debris. C3b or C3(H2O) engages the alternative pathway components, factors B (FB) and D (FD), to form a C3 convertase (C3bBb), which in turn cleaves more C3 to C3b. The binding by another C3b to the C3 convertase generates the C5 convertase (C3bBbC3b). Properdin (P) is a positive regulator that stabilizes both the AP C3 and C5 convertases. The latter subsequently cleaves C5 to release the potent anaphylatoxin C5a, while C5b engages the terminal https://www-uptodate-com.rossuniversity.idm.oclc.org/contents/inherited-disorders-of-the-complement-system/print?search=complement deficiencies&source… 25/32 1/30/24, 11:16 AM Inherited disorders of the complement system - UpToDate pathway and initiates the formation of the lytic membrane attack complex (MAC). The complement system is designed to function most efficiently on a biologic membrane. Graphic 56374 Version 11.0 https://www-uptodate-com.rossuniversity.idm.oclc.org/contents/inherited-disorders-of-the-complement-system/print?search=complement deficiencies&source… 26/32 1/30/24, 11:16 AM Inherited disorders of the complement system - UpToDate Feedback loop of the alternative complement pathway After C3b is generated, it binds to factor B. Factor D can then cleave factor B to form the C3 convertase (C3bBb). The attachment of properdin (P) stabilizes the complex. The end result is the deposition of large amounts of C3b on the pathogen. C3b can be generated by the classical pathway, the lectin pathway, or de novo by the alternative pathway itself. A small amount of autoactivated C3 [called C3(H2O)] is always present and may also bind factor B to engage the alternative pathway. AP: alternative pathway. Adapted from: Liszewski MK, Atkinson JP. The complement system. In: Immunology Scope Monograph, Schwartz, BD (Ed), Upjohn, Kalamazoo, 1992. Graphic 61780 Version 8.0 https://www-uptodate-com.rossuniversity.idm.oclc.org/contents/inherited-disorders-of-the-complement-system/print?search=complement deficiencies&source… 27/32 1/30/24, 11:16 AM Inherited disorders of the complement system - UpToDate Disease-associated inherited deficiencies of complement Protein Gene Inheritance Gene Laboratory OMIM features Diseases Classical pathway C1q C1r C1QA AR 120550 C1QB AR 120570 C1QC AR 120575 C1R AR 613785 CH50 = 0; CP defective activation; Inefficient clearance apoptotic cells SLE; infections with encapsulated organisms CH50 = 0; CP defective activation SLE; infections with encapsulated organisms; EhlersDanlos phenotype C1R AD GOF C1S AR C1S AD GOF C2 C2 AR C4 C4A + C4B AR C1s C3* C3 AR LOF AD GOF Normal CH50 Hyperpigmentation; skin fragility CH50 = 0; CP defective activation SLE; infection with encapsulated organisms; EhlersDanlos phenotype Normal CH50 Hyperpigmentation; skin fragility 217000 CH50 = 0; CP defective activation SLE; infections with encapsulated organisms; atherosclerosis; AMD 120810 + CH50 = 0; CP SLE; infections with 120820 defective activation; biallelic mutations, deletions, or conversions of both C4A and C4B encapsulated organisms; partial or complete C4A deficiency predisposes to SLE 120700 Both CH50 and AH50 = 0; Defective opsonization and humoral immune response Infections; glomerulonephritis Increased complement activation aHUS; AMD 120580 https://www-uptodate-com.rossuniversity.idm.oclc.org/contents/inherited-disorders-of-the-complement-system/print?search=complement deficiencies&source… 28/32 1/30/24, 11:16 AM Inherited disorders of the complement system - UpToDate Lectin pathway MBL MBL2 AD 154545 LP defective activation Increased susceptibility to bacterial infection MASP-2 MASP2 AR 605102 LP defective activation Pyogenic infections; inflammatory lung disease; autoimmunity MASP-3 MASP1 ¶ AR 600521 LP defective activation 3MC1 Collectin (CLL1; CL-K1) COLEC11 AR 612502 LP defective activation 3MC2 Ficolin 3 FCN3 AR 604973 LP defective Respiratory infections activation abscesses AH50 = normal aHUS; AMD AH50 = 0 Infections with encapsulated bacteria Alternative pathway Factor B CFB AD GOF 138470 AR Factor D CFD AR 134350 AH50 = 0 Neisserial infections Properdin CFP XLR 300383 AH50 = 0; need to employ assay that would require properdin Neisserial infections AR 120900 CH50 and AH50 = 0; defective Neisserial infections Membrane attack complex C5 C5 bactericidal activity C6 C6 AR 217050 C7 C7 AR 217070 C8-alpha C8A AR 120950 C8-beta C8B AR 120960 C8-gamma C8G AR 120930 C9 C9 AR 120940 CH50 and AH50 = 0; defective bactericidal activity Reduced CH50 and AH50; deficient bactericidal activity Mild susceptibility to Neisserial infections Regulators and receptors https://www-uptodate-com.rossuniversity.idm.oclc.org/contents/inherited-disorders-of-the-complement-system/print?search=complement deficiencies&source… 29/32 1/30/24, 11:16 AM C1 inhibitor Inherited disorders of the complement system - UpToDate SERPING1 AD 606860 Spontaneous activation of complement; consumption of Hereditary angioedema C4/C2; spontaneous activation contact system; generation of bradykinin from high molecular weight kininogen Factor I CFI AD 217030 AP activation; C3 consumption AR Factor H CFH AD Neisserial infections 134370 AP activation; C3 consumption AR CD46 (membrane cofactor protein) MCP AD LOF AMD; aHUS; preeclampsia AMD; aHUS; preeclampsia Neisserial infections 120920 AR Excessive AP activation; half normal (approximately 75% of cases) to normal levels on PBC via flow cytometry; decreased C3b/C4b binding aHUS; HELLP syndrome; C3G Excessive AP activation; CD46 levels absent CVID CD55 CD55 AR 125240 Hyperactivation of complement on endothelium CHAPLE disease = protein-losing enteropathy; thrombosis CD59 CD59 AR 107271 Erythrocytes highly susceptible to complementmediated lysis PNH-like, hemolytic anemia; polyneuropathy Factor Hrelated protein deficiencies CFHR1 AR or AD 134371 Normal CH50 and AH50; autoantibodies to factor H; linked deletions of one or Older onset aHUS; Neisserial infections CFHR2 600889 CFHR3 605336 https://www-uptodate-com.rossuniversity.idm.oclc.org/contents/inherited-disorders-of-the-complement-system/print?search=complement deficiencies&source… 30/32 1/30/24, 11:16 AM Inherited disorders of the complement system - UpToDate CFHR4 605337 CFHR5 608593 more CFHR genes leads to susceptibility to autoantibodymediated aHUS Receptors CR2 CR2 AR 120650 CR3 (CD11b/CD18) ITGAM + ITGB2 AR 120980 CR4 (CD11c/CD18) ITGAX + ITGB2 AR 116920 CVID Low levels of CD11/CD18 (LFA-1 or leukocyte function antigen-1) glycoprotein LAD I AR: autosomal recessive; CP: classical pathway; AD: autosomal dominant; GOF: gain of function; LOF: loss of function; XLR: X-linked recessive; SLE: systemic lupus erythematosus; aHUS: atypical hemolytic uremic syndrome; LP: lectin pathway; AMD: age-related macular degeneration; MBL: mannose-binding lectin; MASP: mannan-binding lectin-associated protease; 3MC1: name pooled from identical but four separately named disorders; AP: alternative pathway; MAC: membrane attack complex; PBC: peripheral blood cells; HELLP: hemolysis, elevated liver enzymes, and low platelets; C3G: C3 glomerulopathy; CVID: common variable immunodeficiency; CHAPLE disease: CD55 deficiency with hyper-activation of complement, angiopathic thrombosis, and severe protein-losing enteropathy; CR2: complement receptor 2; CR3: complement receptor type 3; CR4: complement receptor type 4; LAD: leukocyte adhesion deficiency 1. * C3 is the central component of all three activation pathways. ¶ MASP-3 is alternatively spliced from the MASP-1 gene. Adapted from: Tangye SG, Al-Herz W, Bousfiha A, et al. Human Inborn Errors of Immunity: 2022 Update on the Classification from the International Union of Immunological Societies Expert Committee. J Clin Immunol 2022. Copyright © 2022 The Authors. Available at: https://link.springer.com/article/10.1007/s10875-022-01289-3 (Accessed on November 10, 2022). Reproduced under the terms of the Creative Commons Attribution License 4.0. Graphic 140105 Version 1.0 https://www-uptodate-com.rossuniversity.idm.oclc.org/contents/inherited-disorders-of-the-complement-system/print?search=complement deficiencies&source… 31/32