- INNATE immune system
- Phagocytic Defects
- Impaired production (Severe congenital neutropenia, SCN)
- Asplenia
- GATA2 Deficiency
- Impaired Adhesion (Leucocyte adhesion deficiency, LAD)
- Mendelian Susceptibility to mycobacterial disease (MSMD)
- Impaired Killing (Chronic granulomatous disease, CGD)
- Invasive Filamentous Fungal Infection common; Also can have invasive candidiasis; However, mucocutaneous candidiasis is NOT seen
- Clinical Correlation:
- Low-grade or transient N. Meningococcal bacteremia is overcome by opsonization and phagocytosis, but higher grader or persistent bacteremia requires the complement system for eradication of invasive disease.
- Innate immunity receptors and signal transduction
- Defects in pattern recognition receptors i.e Cellular receptor that activates innate immune system
- 4 types:
- 2 Membrane bound
- TLR (7 types)
- CLR (5 types)
- CLR are important in recognition of fungi and bacteria in the body NEJM 2011
- 2 Cytoplasmic
- NLR (6 Types)
- NLR recognizes peptidoglycan of bacterial cell wall and activate inflammasome that convert inactive IL 1 and IL 18 to active IL 1 and IL 18.
- RIG - 1 Helicase receptors (2 Types)
- RIG -1 helices receptors are mainly receptors for the nucleic acid of the virus NEJM 2011
- Interaction between TLR and NOD2 is needed for effective innate immunity against mycobacteria, and staphylococci. NEJM 2011
- Likewise, cross talk between CLR and TLR is needed for anti-fungal innate immunity NEJM 2011
- Defect in IFN Gamma Pathway (Mycobaterial and Salmonella Susceptibility )
- Complement Deficiencies
- Classic, Alternate, Lectin pathways
Molecules Great and Small: The Complement System CJSAN 2015- Clinical Pearls
- Defect in MBL pathway deficiency can lead to recurrent strep bacteremia
- Deficiency of C3 can also lead to recurrent strep bacteremia
- Later 2 are part of innate immune system as they act as first line defense before antibody is formed
- IgM and IgG can only activate complement system, hence cryoglobulinemic disorders are either IgG or IgM mediated.
- Normal C3 does not rule out Alternate Pathway Activation.
- In some cases, as in some cases of MPGN, immune-complex may initiate the disease process but the disease may be accelerated by alternate pathway (MPGN - A New Look at an Old Entity NEJM 2012)
Case 3-2014: A 61-Year-Old Woman with Gastrointestinal Symptoms, Anemia, and Acute Kidney Injury (RPGN):
Causes of RPGN
- a) Anti - GBM
- b) ANCA Vasculitis
- c) Immune complex disease
- Low Complement Immune Complex Disease
- Alternate Pathway (Normal C4, Depressed C3; decreased Factor B)
- Usually uncommon in clinical medicine
- Pediatric renal diseases MPGN, C3 Glomerulopathies,
- IgG 2 and IgG 4 do not activate classic pathways, and upon binding to protein can activate alternate pathway. This can sometime happen in SLE
- Also involved during or by Dialysis, some microbes,
- aHUS
- Classic Pathway (Depressed C4, Normal or Low C3)
- Cryoglobulinemia
- SLE
- Post-streptococcus GN
- Endocarditis
- MPGN
- Normal Complement Immune Complex Diseases
- Ig A Nephropathy IgA Nephropathy NEJM 2013
- HSP (Henoch-Scholein Purpura)
- Fibrillary GN (Polyclonal Gammopathy), Immunotactoid GN (Monoclonal Gammopathy)
- Lytic phase
Case 23-2009: A 13-Y-O Boy with Headache, Nausea, Seizures, and HTN (Atypical Hemolytic syndrome)
Case 22-2011: A 79-Year-Old Man with a Rash, Arthritis, and Ocular Erythema (Hypocomplimentic Urticarial Vasculitis)
Case 11-2015: A 28-y-o-W with HA, Fever, and a Rash (Complement Deficiency and recurrent meningitis)
Acquired causes of low complement values (classic pathway) Up-to-Date
- Lab Evaluation
- Alternate Pathway:
- C3, C4, serum MAC, an alternate pathway functional assay, hemolytic complement assays (all in the initial assay) (MPGN - A New Look at an Old Entity NEJM 2012)
- Once Alternate Pathway Involvement is confirmed further tests can be done including genetic analysis, auto-antibiodies
- AH 50 (assay for alternate complement pathway activity):
- Low AH50 level together with low CH 50 level and normal C3, C4, Factor B suggests the deficiency in terminal complement component
- Evaluation for Terminal Complement Pathway
- Assay for total hemolytic complement i.e CH50 (Done after patient recovers from the current illness)
- If CH50 is low in a patient with normal C3, then individual terminal complement components are tested (C5, C6, C7, C8, C9; Note: C9 deficiency is not associated with recurrent Meningococcal meningitis)
- If complement component deficiency is noted then testing should be offered to immediate relatives
- Complement Deficiency Medscape 2015
- Complement-Related Disorders Medscape 2015
- Acquired disorders of the complement system UpToDate
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