Immunology 1a Flashcards
Auto-inflammatory vs auto-immune disease and mechanism
If driven by abnormalities in the innate immune system = auto-inflammatory disease
- Inappropriate activation of innate immune cells (i.e. macrophages) resulting in tissue damage
If driven by abnormalities in adaptive immune system = auto-immune disease
- Aberrant T and B cell responses in primary and secondary lymphoid organs → breaking of tolerance with development of immune reactivity towards self-antigens
- Adaptive immune response plays the predominant role in clinical expression of disease
- Organ-specific antibodies may predate clinical disease by years
- Monogenic diseases are rarer
Clinical immunology
Primary vs secondary immunodeficiencies
Primary = inherited
- rare
Secondary = acquired
- common
- often subtle
- often involves more than one component of the immune system
examples of secondary immunodeficiencies
What are physiological immunodeficiencies
to be expected
neonates, pregnancy, old age
clinical features suggestive of immunodeficiency and of primary immunodeficiency
Infections
- 2major or one major and one recurrent minor in one year
- unusual organisms
- unusual sites
- unresponsive to treatment
- chronic infections
- early structural damage
Other features suggestive of primary immune deficiency
- FHx
- young age at presentation
- failure to thrive
Cells and soluble components of the innate immune system
Cells
Polymorphonuclear cells – neutrophils, eosinophils, basophils Monocytes and macrophages
Dendritic cells
Natural killer cells
Soluble components
Complement
Acute phase proteins Cytokines and chemokines
Phagocytes (5 features)
what are the two types?
Identical responses in all individuals
Express cytokine/chemokine receptors to home to sites of infection
Express genetically encoded receptors to allow detection of pathogens at site of infection
- PRRs (toll-like receptors or mannose receptors) which recognise PAMPS such as bacterial sugars, DNA, RNA
Express Fc receptors to allow detection of immune complexes
Have phagocytic capacity to engulf pathogens
Secrete cytokines and chemokine to regulate immune responses
2 types:
- polymorphonuclear cells (granulocytes): neutrophils, eosinophils and basophils/mast cells
- mononuclear cells: monocytes and macrophages
Polymorphonuclear cells (granulocytes): examples, production and function
Neutrophils, Eosinophils and Basophils/Mast cells
Produced in bone marrow and migrate rapidly to site of injury
Release enzymes, histamine, lipid mediators of inflammation from granules
Mononuclear cells: examples (in certain areas), production and function
Monocytes and Macrophages
Monocytes are produced in bone marrow, circulate in blood and migrate to tissues where they differentiate to macrophages
Capable of presenting processed antigen to T cells
Innate immune response mechanism
What are the 4 types of phagocyte deficiency?
- Failure to produce neutrophils
- Defect of phagocyte migration
- Failure of oxidative killing mechanisms
- Cytokine deficiency
Phagocyte deficiency: failure to produce neutrophils
Failure of stem cells to differentiate along myeloid or lymphoid lineage
- Reticular dysgenesis – autosomal recessive severe SCIDmutation in mitochondrial energy metabolism
- enzyme adenylate kinase 2 (AK2)
Specific failure of neutrophil maturation
- Kostmann syndrome - autosomal recessive severe congenital neutropenia
Classical form due to mutation in HCLS1-associated protein X-1 (HAX1)
- Cyclic neutropenia - autosomal dominant episodic neutropenia every 4-6 weeks
- mutation in neutrophil elastase (E_LA-2)_
Phagocytic deficiency: Defect of phagocyte migration
Leukocyte adhesion deficiency
- deficiency of CD18 (B2 integral subunit)
- CD11a/CD18 (LFA-1) expressed on neutrophils, binds to ligand (ICAM-1) on endothelial cells and so regulates neutrophil adhesion/transmigration
- neutrophils lack adhesions molecules and fail to exit from the bloodstream
- very high neutrophil counts in blood
- absence of pus formation
Phagocyte deficiency: failure of oxidative killing mechanisms
Chronic granulomatous disease
Absent respiratory burst
- deficiency of component of NADPH oxidase
- inability to generate oxygen free radicals results in impaired killing
Excessive inflammation
- persistent neutrophil/macrophage accumulation
- failure to degrade antigens
Granuloma formation
Lymphadenopathy and hepatosplenomegaly
Chronic granulomatous disease Ix
DHR and NBT tests (both -ve in CGD)
Phagocyte deficiency: cytokine deficiency
IL12, IL12R, IFNy or IFNyR deficiency
IL12 - IFNy network important in control of mycobacteria infection
- Infected macrophages stimulated to produce IL12
- IL12 induces T cells to secrete IFNg
- IFNg feeds back to macrophages &
- neutrophils
- Stimulates production of TNF
- ActivatesNADPHoxidase
- Stimulates oxidative pathways
Phagocyte deficiencies lead to what infections?
Recurrent infections - skin/mouth
- bacterial = staph aureus, enteric bacteria
- fungal = candida, aspergillus fumigatus and flavus
Mycobacterial infection
- MTB
- Atypical mycobacteria
Investigation of phagocyte deficiencies
Treatment of phagocyte deficiencies
Agressive management of infection
- infection prophylaxis e.g. abx (septrin) anti-fungals (itraconazole)
- oral/IV abx as needed
Definitive therapy
- HSCT
- specific tx for CGD = interferon gamma therapy
NK cells
NK cells deficiencies (2 types)
Classical NK deficiency
- absence of NK cells within peripheral blood
- abnormalities in GATA2/MCM4 genes in subtypes 1 and 2
Functional NK deficiency
- NK cells present but function in abnormal
- Abnormality described in FCGR3A gene in subtype 1
NK cell deficiencies lead to what infections?
virus infection:
- Herpes virus infection = Herpes Simplex virus I and II
- Varicella Zoster virus
- Epstein Barr virus
- Cytomegalovirus
- Papillomavirus infection
NK cell deficiencies tx
No good trial data
prophylactic antiviral drugs such as acyclovir or gancyclovie
cytokines such as IFN-a to stimulate NK cytotoxic function
HSCT in severe phenotypes
Match up!
Young child with recurrent infections. High neutrophil count on FBC but no abscess formation.
Leukocyte adhesion deficiency
Child with recurrent infections with hepatosplenomegaly and abnormal dihydrorhodamine test (does not fluoresce).
Chronic granulomatous disease
Baby with recurrent infections and no neutrophils on FBC.
Kostman syndrome
Young man with infection with atypical mycobacterium. Normal FBC.
IFN-y receptor deficiency
Child with severe chicken pox and disseminated CMV infection → Classical NK cell deficiency
Complement: structure, production, function
3 pathways of complement activation
Pathways of complement activation: classical pathway
Formation of antibody- antigen immune complexes
Results in change in antibody shape – exposes binding site for C1
Binding of C1 to the binding site on antibody results in activation of the cascade
Dependent upon activation of acquired immune response (antibody)
Pathways of complement activation: mannose binding lectin pathway
Activated by direct binding of MBL to microbial cell surface carbohydrates
Directly stimulates the classical pathway involving C4 and C2 but not C1
Not dependent on acquired immune response
pathways of complement activation: alternate pathway
Bacterial cell wall fails to regulate low level of spontaneous activation of alternative pathway
- e.g. lipopolysaccharide of G-ve bacteria
- teichoic acid of G+ve bacteria
Not dependent on acquired immune response
Involves factors B,D and Proepridin
Factor H - control protein
Pathways converge on activation of C3
Activation of C3 is the major amplification step in the complement cascade
Triggers the formation fo the MAC via C5-C9
Role of complement fragments (5)
Increases vascular permeability and cell trafficking to site fo inflammation
Opsonisation of pathogens to promote phagocytosis
Activates phagocytes
Promotes mast cell/basophil degranulation
Punches holes in bacterial membranes
Promotes clearance of immune complexes
Deficiency of complement
May involve 3 pathways or final common pathway
Susceptibility to bacterial infections
Especially encapsulated bacteria (NHS)
- Neisseria meningitides = esp. properdin and C5-C9 deficiency
- Haemophilus Influenzae
- Streptococcus pneumoniae
→ CAN LEAD TO MENINGOCOCCAL SEPTICAEMIA
MBL deficiency
- MBL2 mutations common but not usually associated with immunodeficiency
Deficiencies of early classical component pathway components are associated with? Which complement?
SLE
C1q, C1r, C1s, C2, C4 deficiency are all described
– All are rare
– C2 deficiency most common
Clinical phenotype
- Almost all patients with C2 deficiency have SLE
- Usually have severe skin disease
- Also have increased incidence of infection
Active lupus causes persistent production of immune complexes and consequent consumption of complement leading to functional complement deficiency → SECONDARY COMPLEMENT DEFICIENCY
What are examples of secondary complement deficiencies?
Glomerulonephritis via nephritic factors (auto-antibodies, leads to 3 activation and consumption)
Investigation of the complement pathway
Quantification of complement components
- C3, C4 routinely measured
- C1 inhibitor → decreased in hereditary angiodema
- other components not routinely quantified, but can be performed if deficiency is suspected
Functional complement tests
- CH50 classical pathway
- AP50 alternative pathway
Management of patients with complement deficiencies
Vaccination
- boost protection mediated by other arms of the immune system
- meningovax, pneumovax and HIB vaccines
Prophylactic abx
Treat infection aggressively
Screening of family members
MATCH UP
Meningococcus meningitis with FHx of sibling dying of same condition aged 6 → C7 deficiency
Membranoproliferative nephritis with abnormal fat distribution → C3 deficiency with presence of a nephritic factor
Severe childhood onset SLE with normal levels of C3 and C4 → C1q deficiency
Recurrent infections with neutropenic following chemotherapy but previously well → MBL deficiency
Types of primary immunodeficiency examples
