Immunology Flashcards
What pathology are TLRs involved in?
Gran negative sepsis
Immunodeficiency
Autoimmunity
Vaccinations (enhance effect)
What does TLR3 deficiency put someone at risk of?
HSV1 encephalitis
What does IRAK4 deficiency put someone at risk of?
Recurrent pyogenic infections
What do NOD-like receptors do?
Monitor cytoplasm for foreign or danger signals via:
1. Assembly of inflammasome
2. Direct recognition and signalling
Role of inflammasomes
Sense DAMPs and PAMPs then activate Capsase-1, causing release of IL-1 and IL-18
Role of c-type lectins
Glue that sticks to pathogens
Mediates phagocytosis
Role of IL-1
Pro-inflammatory released on inflammasome activation
-Increased expression of adhesion molecules
-Fever
-Stimulates IL-6 production
Excessive release in gout (inflammasome mediated disease)
Role of plasmacytoid dendritic cell
Repsond to viral infection
Release lots of type 1 IFN - induce rapid antiviral state
Role of complement systems
Cytolysis
Opsonisation
Activation of inflammatory response - release of anaphylatoxins
Immune complex clearing
Activation of alternate pathway
Spontaneous!
C3 spontaneously activates to C3b
Then binds to a foreign surface if present, and then activates alternate pathway
Activation of classical pathway
Initiated by C1q
-Activated by IgM and IgG
Lectin pathway activation
Activated by mannose-binding lectin and ficolins. Lectin associates with MASP1 and 2
On activation, cleaves C4 and C2
C1 esterase inhibitor role
Binds to C1r:C1s and causes them to dissociate from C1q
-Limits the available time for them to activate C4 and C2
-Acts to control coagulation system and generation of bradykinin
Result of lack of C1:INH
Uncontrolled activation of C1 –> activation and consumption of C4 and C2 (not C3) –> excessive generation of factor 12a and kallikrein –> increased bradykinin release –> increased capillary permeability –> oedema
Hereditary angioedema
Autosomal dominant
Hemizygous def of C1:inh leading to increased classical complement pathway activation
Hereditary angioedema presentation and management
Recurrent attacks of oedema, non-pruritic, non-urticarial, onset school age. Resolve within 72 hours.
Can be hereditary or acquired (lymphoproliferative disorders 50%!, autoimmune disease).
Acute management:
-Replace C1:INH if life-threatening
-Bradykinin-2 receptor antagonist: Icatibant
Preventative management:
-Anabolic steroids: danazol
-TXA
-C1:inh regular infusionsH
Hereditary angioedema bloods
Decreased C4, normal C3
Decreased C1:inh levels in hereditary type 1
Abnormal functional C1:INH assay in all
Decreased C1q in acquired forms (consumption)
Chronic granulomatous disease pathology
Deficiency of 1 of 4 subunits of NADPH oxidase (responsible for respiratory burst in neutrophils and necessary for killing intracellular organisms)
Chronic granulomatous disease infections
Staph and aspergillus
Infections of skin, lung, LNs (often granulomatous), gut (C.D)
Chronic granulomatous disease investigation
NBT test: measure oxygen free radicals from granulocytes or flow cytometry
What region does isotype switching occur at?
S region
Leads to affinity maturation/somatic hypermutation and development of Igs that may have better affinity for a target
CVID associations
10% familial
Often associated with IgA deficiency
CVID clinical features
Recurrent sinopulmonary infections
Gut infections (giardia, campylobacter)
Skin infections (boils)
Autoimmnity
Cancer (lymphoma + gastric ca. 40x risk of NHL!!)
Lymphoproliferation
BronchiectasisC
CVID blood tests
Marked decrease in IgG +/- low IgA and IgM. Two occasions 1 hr apart, when infection free.
AND one of:
-Poor response to vaccines
-IgG <2g/L and delay to replacement would cause risk
-Low switched memory B cells
-Absent isohaemagglutins
AND
-diagnosis after 4th year of life
Need to exclude secondary causes: SPEP/FLC/whole body CT
CVID treatment
Replace IgG
-Aim trough level 7g/L
-Adjust based on level and breakthrough infections
ABx for infections (early and longer)
Avoid live vaccines
Assess for complications: HRCT, PFTs, enteropathy
X-linked agammaglobulinaemia (Bruton’s) pathology and age of onset
Mutation in BTK
FHx in 50%
Onset approx 6 months of age
X-linked agamma presentation
Recurrent infections
Malabsorption
Polyarthropathy (RA)
Neutropenia (often with infection)
Chronic echovirus meningoencephalitis
X-linked agamma bloods
Hypogammaglobulinaemia - Ig undetectable
B cell count = 0
No plasma cells or germinal centres on biopsy
B cell precursors present in marrow
Genetic analysis of BTK gene
Treat same as CVID
IgA deficiency pathology and causes
Absence of IgA +/- IgG subclasses due to dysregulation in Ig isotype switching during B-cell activation
Causes:
Mostly sporadic
Drug induced (phenytoin, penicillamine)
Intra-uterine infection
IgA deficiency presentation
Any age
Mucosal infections - sinopulmonary + gut (Giardia)
IgA deficiency associations
Atopic diseases
Cow’s milk allergy
GIT disease (IBD, coeliac)
AI disorders
Anaphylaxis
Lymphoreticular malignancy
IgA deficiency labs
Decreased IgA. Normal B cells, normal EPG
IgA deficiency management
Prompt Abx
IVIG NOT given - ONLY if associated IgG deficiency
Should transfuse with blood from an IgA deficient donor or triple wash cells
Specific Ab deficiency presentation and bloods
Recurrent URTIs in childhood
All Ig levels are normal and B cells present
Specific Ab to vaccination impaired
Treatment
-Vaccination
-Prophylactic Abx
-IVIG
T cells receptor structure
Two chains (a + b) always membrane bound, never secreted unlike Ig from B cells
Variable and constant regions
Function of AIRE
Autoimmune regulator
Turns on expression of tissue specific Ags at low levels in thymus
–> delegation of high affinity T cells
–> induction of thymic regulator cells
Autoimmune Polyendocrine Syndrome Type 1 (APECED) (with candiasis and ectodermal dystrophy pathology
Genetic disorder due to mutated AIRE gene (mostly autosomal recessive)
Defective AIRE –> defective central tolerance –> auto reactive T cells released into periphery –> Autoimmunity
APECED 3 cardinal manifestations
Autoimmune hypoparathyroidism
Autoimmune Addison’s disease
Chronic mucocutaneous candidiasis (IL17, IL22)
What is signal 1 in T cell activation and co-stimulation?
MHC and peptide
What is signal 2 in T cell activation and co-stimulation
Co-stimulation
B7.1 (CD80) and B7.2 (CD86) interact with CD28 on T cells –> activation and CTLA4 on T cells –> delayed deactivation
Abatacept MOA
CTLA4-Ig
Causes B7 blockade on T cell leading to prevention of T cell activation (signal 2)
Ipilimumab MOA
Anti-CTLA4
Prevents CTLA4 from blocking T cell activation
Where does CD40:CD40L co-stimulation occur?
B cell: T cell
Hallmark of Hyper IgM syndrome
CD40L deficiency
Function of IL2
Drives T cell expansion
Treg cell markers
CD4+
CD25
FOXP3 expression
IPEX syndrome pathology
Defect of FOXP3
Leads to immune dysfunction, polyendocrinopathy, enteropathy, x-linked
Frequently fatal, presents in first few months.
Th1 cells differentiation and function
Differentiate in response to IL-12 and IFN-y
Secrete IFN-y, TNF, lymphotoxin leading to activation of macrophages + NK cells, act on B cells to increase Ab formation, defence against intracellular pathogens
Mandelian susceptibility to mycobacterial disease
Genetic deficiency of various Th1 pathway components
Susceptibility to:
-Non-TB myco
-BCG vaccine
-Invasive salmonellosis
-Tb
-Severe viral infection
TH17 cells differentiation and function
Differentiate in response to TGF-b, IL6/IL1
Il23 is a cardinal cytokine in Th17 expansion
Secrete IL-17 (and 22) –> pro-inflammatory
Defence against candida, staph
Th17 cells drive psoriasis
Defect that is common in chronic mucocutaneous candidiasis
Often lack Th17 cells
Th2 cells differentiation and function
Differentiate in response to IL-4
Secrete IL4, IL5, IL13
Role in atopic-type response
-IgE production by B cells (IL4,13)
-Eosinophils (IL5)
-More naive T cells induced to Th2 cells
Defence against Helminths
Cytotoxic T cells activation and function
Activated by dendritic cells
Kill viral infected target cells mostly by perforin-granzyme
Consequence of lack of T cells
Infection with intracellular organisms
-Fungi (Candida)
-Viruses (CMV, HSV, VZV, Protozoa, listeria)
-Mycobacterium (MAC, Tb)
Combined immunodeficiency
Not severe like SCID
Like CVID (Ab def) + T cell infections (e.g. mycobacterium, fungal, PJP)
Worse prognosis than CVID
Tx as per CVID
What is idiopathic CD4 T cell lymphopenia
CD4 <300 or 20% of lymphocytes (twice, 6 weeks apart)
HIV seronegative. No secondary cause. Opportunistic infections (need prophylaxis)
What is SCID
Presents in kids
Failure to thrive, chronic diarrhoea
Recurrent opportunistic infections (+ malignancy + AI risk)
Role of HLA antigens
Set of highly polymorphic proteins on cell surface
Role is presentation of peptides to T cells
Which cells are HLA class 1 present on and what does it do
On all cells except RBCs and some neuronal cells
Present antigen (from degraded intracellular proteins i.e. viruses/bacteria) to CD8 T cells
Which cells are HLA class 2 present on and what is its function
Only expressed by specialised dendritic cells
Present antigen (derived from degraded extracellular proteins) to CD4 T cells (binds to B2 domain)
How to NK cells do their killing?
Via Antibody-dependent cell-mediated toxicity
Kill cells that have lost MHC expression e.g. tumour cells
Release IFN-y to activate innate immune system
Major cell of the pregnant uterus
Tezepelumab MOA
Anti-TSLP
-Decrease asthma exacerbations
-Decrease IgE and eosinophils
-Increase FEV1
