Immuno Flashcards
Clinical Features suggesting immunodeficiency
x2 major or x1 major and recurrent minor infections in one year
unusual organisms unusual sites unresponsive to tx chronic infections early structural damage
Clinical Features suggesting PRIMARY immunodeficiency
Family hx
Young age at presentation
Failure to thrive
Reticular Dysgenesis
Severe SCID Failure of stem cell differentiation (myeloid or lymphoid lineage) Fatal (BM transplant) Autosomal recessive Mutation: AK2
Kostmann Syndrome
Severe congenital neutropenia
Specific failure of neutrophil maturation
Autosomal recessive
Mutation: HAX-1
Cyclic Neutropenia
Episodic neutropenia (4-6w)
Specific failure of neutrophil maturation
Mutation: ELA-2
Leukocyte adhesion deficiency
CD18 deficiency (b2 subunit)
Normally - CD11a/CD18 (LAD1) on neutrophil binds endothelial ligand (ICAM-1) to allow transmigration into tissues.
Very high neutrophil count (blood)
No pus formation
Delayed umbilical cord seperation
Chronic Granulomatous Disease
NADPH oxidase component deficiency
Impaired oxidative killing of pathogens
Granuloma formation
Lymphadenopathy and HSM
Chronic Granulomatous Disease - susceptible pathogens
Catalase positive bacteria - PLACESS
Pseudomonas Listeria Aspergillus (fungal) Candida (fungal) E. Coli Staph A Serratia
Chronic Granulomatous Disease - tests and management
Presence of hydrogen peroxide
NBT - yellow to blue colour change
DHR - oxidsed to rhodamine (strongly fluorescent)
NEGATIVE
Specific tx - IFNgamma therapy
IL12 (IL12R) and IFNy (IFNyR) Deficiency
Specific immune deficiency
Organisms affected by macrophages
Atypical mycobacteria and salmonella
Infected macrophage secretes IL-12 (acts on T cell)
T cell secreted IFNy
Stimulates macrophage to produces TNF
Activates NADPH oxidase
Classical NKC deficiency
Absent NKC in peripheral blood
Mutations: GATA2 and MCM4 in subtypes 1 and 2
Functional NKC deficiency
Abnormal NKC function
Mutations: FCGR3A in subtypes 1
NKC deficiency - infections
Increased risk of viral infections
HSV1 + 2, VZV (recurrent, EBV, CMV, papillomavirus (uncontrolled, multiple infections)
NKC deficiency - treatment
Prophylactic antivirals (acyclovir, gancyclovir) Cytokine therapy - TNF alpha stimulates cytotoxic function (in functional deficiency) Stem cell transplant for severe phenotype
Complement Deficiencies (any defect)
Inability to make MAC Increased risk of encapsulated bacteria Neiserria meningitidis Strep pneumoniae Haemophilus influenzae
Classical Complement Pathway Deficiency
C1, C2, C4
Classical pathway stimulated by immune complex binding
Rare deficiency (C1q, C1r, C1s, C2, C4)
C2 most common
Deficiency leads to deposition of immune complexes and increased load of self-antigens - leads to SLE
Secondary Classical Complement Pathway Deficiency
Persistent production of immune complexes in SLE leads to depletion of classical complement
MBL Deficiency
MBL2 mutaition = common but not usually a/w immunodeficiency
30% heterozygous for mutant protein
6-10% have no circulating MBL
A/w increased risk of infection if another cause of immune impairment
- prem infant, chemo, HIV, Ab deficiency
C3 Deficiency
C3 Deficient - Meningococcus, streptococcus, haemophilus
Increased risk of connective tissue disorder
Secondary C3 Deficiency
Nephritic factors act as auto-Ab
Stabilise C3 convertase - C3 activation and consumption
A/w glomerulonephritis (membranoproliferative)
May be a/w partial lypodystrophy
Alternate Pathway Deficiencies
Factors B/I/P (Properidin)
unable to rapidly mobilise complement
encapsulated bacteria infections (recurrent)
Testing for Complement Deficiencies
CH50 - classical pathway
AP50 - alternative pathway
Both - common pathway
Complement Deficiencies Management
Vaccination - against meningococcus (Meningovax), pneumococcus (Pneumovax), Haemophilus (HIB)
Prophylactic abx - usually penicillin
Treat infection aggressively
Screen family members (C7, C9 deficiency)
Hereditary angiodema
Decreased C1 inhibitor
SCID
<3m protected by maternal IgG
Present with infections (all types), failure to thrive, persistent diarhhoea
graft vs host disease - BM colonised by maternal lymphocytes - presents with unusual skin rash
X-Linked SCID
Most common SCID (45%)
Mutation on gamma chain chr 13.1
Shared by IL-2, IL-4, IL-7, IL-9,IL-15, IL-21
Very low/ absent T cell numbers
Normal or increased B cell numbers
Poorly developed lymphoid tissue and thymus
ADA Deficiency SCID
16.5% of all SCID
Adenosine Deaminase = required for lymphocyte cell metabolism
Very low/ absent T cell, B cell and NKC numbers
Tx: enzyme replacement (PEG-ADA for ADA SCID)
CD8+ T cells
Recognise intra-cellularly derived peptides in association with HLA Class I (HLA-A, HLA-B, HLA-C)
Kill cells directly (perforin)
Expression of Fas ligand - apoptosis
Defence against viral infections and tumours
CD4+ T cells
Recognised peptides derived from extracellular poteins in association with HLA Class II (HLA-DR, HLA-DP, HLA-DQ)
Immunoregulatory function via cell:cell interactions/ expression of cytokines
Help develop B cell response
Help for some CD8+ responses
CD4+ T cell subtypes - Th1
Help CD8 T cells and macrophages
Intracellular pathogens
IL-2, IFNy, TNFa, IL-10
CD4+ T cell subtypes - Th17
Neutrophil recruitment
Extracullular pathogens
Inflammatory disease
IL-17, IL-21, IL22
CD4+ T cell subtypes - Treg
IL-10/ TGF beta expressing
CD25+
Foxp3+
CD4+ T cell subtypes - TFh
Follicular helper T cells
B cell response - germinal centre (differentiation into memory/ plasma cells - class switching)
IL-2, IL-10, IL-21
CD4+ T cell subtypes - Th2
Helper T cells
Helminth parasite
DiGeorge Mutation
Deletion at 22q11.2
TBX1 may be responsible (usually sporadic)
Pharyngeal pouch developmental defect
DiGeorge features
CATCH-22 Cardiac abnormalities (ToF) Abnormal facies (high forehead, low set ears) Thymic aplasia (T cell lymphopenia) Cleftpalate Hypocalcaemia/hypoPTH 22- chromosome
Bare Lymphocyte Syndrome (BLS) Type 2
MHC Class II expression needed to select CD4+ cells
Profound CD4+ deficiency
Defect in class II gene expression regulatory proteins:
- Regulatory Factor X
- Class II transactivator
CD4+ required for GC class switching
Normal numbers of CD8+ and B cells (do not differentiate into plasma cells)
Failure to make IgG/ IgA
May be a/w sclerosing cholangitis
BLS Type I
Failure to express MHC Class I
Profound CD8+ deficiency
T Cell Function Disorders
Deficiency of IFNy and IL-12 (and their receptors)
T-B cell communication disorder
Hyper IgM Syndrome
Failure to express CD40L
Clinical features of T cell deficiency
Viral infections - CMV
Fungal infection - PCP, cryptosporidium
Some bacterial infections (intra-cellular orgnanisms) - TB, Salmonella
Early malignancy
Investigations for T cell deficiencies
Total WCC (lymphocyte count higher in children)
Quantify: CD8, CD4, B cells and NK cells
Ig: CD4+ deficienct = IgG and IgA deficient (IgM = normal)
Functional tests
HIV test
Treatment for T cell deficiencies
Aggressive infection prophylaxis/ tx
SCID and BLS - stem cell transplant
Enzyme replacement: PEG-ADA for ADA SCID
Gene therapy - stem cells ex-vivo tx with viral vectors containing missing components
Thymic transplant - T cell differentiation in DiGeorge (cultured donor thymic tissue transplanted into quadriceps muscle)
B cell reactions
- Early IgM response (T cell independent) - differentiate to produce IgM memory cells, Ab secreting plasma cells
- GC reaction (CD4+ T cell dependent)
Dendritic cells prime CD4+ cells
CD4+ help B cell differentiation (CD40L:CD40)
B cell proliferation and class switching = high affinity memory/ plasma cells
Immunoglobulins
IgM = pentamer IgA = dimer
Heavy chain = class Fab domain = recognises antigen Fc domain determines function (bound by complement, phagocytes, natural killer cells)
Bruton’s X Linked Hypogammaglobinaemia
Abnormal B-cell tyrosine kinase (BTK) - cannot mature
Absent mature B cells no circulating Ig after 3m
Boys present with recurrent bacterial infections (OM, sinusitis, pneumonia, ostemyelitis, SA, gastroenteritis)
Failure to thrive
Also viral/fungal/parasitic infections - enterovirus, PCP
Hyper IgM Syndrome
X-linked recessive
Mutation in CD40L gene (Xq26)
CD40L expressed by activated T cells and interacts with CD40 on B cells/ APCs
Elevated IgM (absent IgG, IGA, IgE) Normal number of B cells
Selective IgA Deficiency
1:600
2/3 asymptomatic
1/3 recurrent resp infections (+ GI infections)
unknown cause
Common Variable Immune Deficiency definition
1, Marked reduction in IgG (also low IgA, IgE)
- Poor/ absent response to vaccination
- Absence of other defined deficiency
Recurrent bacterial infections with severe end organ damage (bronchiectasis)
AI disease
Granulomatous disease
Clincial Features of Ab Deficiency (or CD4 T cell deficiency)
bacterial infections - steph, strep
toxins - tetanus, diptheria
some viral infections - enterovirus
Muckle Wells Syndrome
Monogenic Auto-inflammatory
Gene: NLRP3 - Gain of function
Protein: NALP3
Inheritance: Cryopyrin
Autosomal dominant
Familial cold auto-inflammatory syndrome
Monogenic Auto-inflammatory
Gene: NLRP3 - Gain of function
Protein: NALP3
Inheritance: Cryopyrin
Autosomal dominant
Chronic infantile neurological cutaneous articular syndrome
Monogenic Auto-inflammatory
Gene: NLRP3 - Gain of function
Protein: NALP3
Inheritance: Cryopyrin
Autosomal dominant
TNF receptor associated periodic syndrome
Monogenic Auto-inflammatory
Gene: TNFRSF1
Protein: TNF receptor
Inheritance: Autosomal dominant
Hyper IgD with periodic fever syndrome
Monogenic Auto-inflammatory
Gene: MK
Protein: Mevalonate kinase
Inheritance: Autosomal recessive
Familial mediterranean fever
Monogenic Auto-inflammatory
Gene: MEFV
Protie: Pyrin-marenostrin
Inheritence: Autosomal recessive
Familial Mediterranean Fever (Pathogenesis)
Pyrin-marenostrin expressed mainly in neutrophils
Failure to regulate cryopyrin driven activation of neutrophils
Intermittent episodes of inflammation
Familial Mediterranean Fever (Clinical presentation)
Periodic fevers lasting 48-96 hours associated with:
Abdominal pain due to peritonitis
Chest pain due to pleurisy and pericarditis
Arthritis
Rash
Familial Mediterranean Fever - long term risk
Long term risk of AA amyloidosis
Inflammation stimulates liver to produce serum amyloid A (acute phase protein)
Deposits in kidneys, liver, spleen
kidney - most clinically important
Proteinuria with development of nephrotic syndrome
Renal failure
Familial Mediterranean Fever
Colchicine 500ug bd - binds to tubulin in neutrophils and disrupts neutrophil functions including migration and chemokine secretion
Most controlled on colhicine alone
Anakinra (Interleukin 1 receptor antagonist)
Etanercept (TNF alpha inhibitor)
APS1/ APECED
Autosomal recessive
Defect in ‘auto-immune regulator’ – AIRE
Leads to failure of central tolerance
Autoreactive T and B cells
AIRE
auto-immune regulator
TF involved in T cell tolerance (thymus)
Upregulates expression of self-antigens by thymic cells
Promotes T cell apoptosis (death of auto reactive T cells)
APS1/ APECED - presentation
Multiple auto-immune diseases: Hypoparathyroidism Addisons Hypothyroidism Diabetes Vitiligo Enteropathy
Antibodies vs IL17 and IL22 = Candidiasis
IPEX
Mutations in Foxp3 -required for Treg cell development
Fail to negatively regulate T cell responses = autoAb formation
IPEX - presentation
Autoimmune diseases Enteropathy Diabetes Mellitus Hypothyroidism Dermatitis – eczematous rash with high IgE
Diarrhoea Diabetes Dermatitis
ALPS
More common
Mutation: FAS pathway
Eg TNFRSF6 mutation (encodes FAS)
Heterogeneous depending on the mutation
Defect in apoptosis of lymphocytes
Failure of tolerance
Failure of lymphocyte ‘homeostasis’
ALPS - Presentation
++ lymphocyte numbers
large spleen/ LN
Double negative (CD4-CD8-) T cells
Commonly auto-immune cytopenias
Lymphoma – failure to control T cell proliferation
Crohns Disease
NOD2 gene mutation (CARD-15, IBD-1) in 30%
1 abnormal allele - 1.5-3x risk
2 abnormal alleles - 14-44x risk
Expressed in cytoplasm of macrophages/ neutrophils/ dendritic cells
Precise mechanism unknown – thought to effect the capacity of cells expressed in the gut to sense microbes which leads to abnormal inflammatory response
Crohns Disease - Treatment
Corticosteroid
Azathioprine
Anti-TNF alpha antibody
Anti-IL12/23 antibody – more recent anti-IL 23 probably important
Ankylosing Spondylitis - genes
IL23R (IL-23 promotes Th17 cell differentiation - secrete IL-17) ERAP1 (ARTS1) ANTXR2 ILR2 HLAB27
Ankylosing Spondylitis - Presentation
Low back pain and stiffness
Large joint arthritis
Enthesitis
Uveitis
Ankylosing Spondylitis -Treatment
Non-steroidal anti-inflammatory drugs
Immunosuppression – block TNF alpha pathway
Anti-TNF alpha
Anti-IL17 – recent (see mutations IL23R)
Anti-IL12/23
Goodpastures HLA
HLA-DR15
Graves Disease HLA
HLA-DR3
SLE HLA
HLA-DR3
T1DM HLA
HLA-DR3/4
RA HLA
HLA-DR4
PTPN22
Suppresses T cell activation
Mutations in SLE, T1DM, RA
CTLA4
Regulates T cell activation
Mutations in SLE, T1DM, Autoimmune Thyroid Disease, (RA)
Type I Hypersensitivity
Type I: Immediate hypersensitivity which is IgE mediated
Rapid allergic reaction
Pre-existing Ig E antibodies to allergen
Ig E bound to Fc epsilon receptors on mast cells and basophils = cell degranulation
Inflammatory mediators
Pre-formed: Histamine, serotonin, proteases
Synthesised: Leukotrienes, prostaglandins,
bradykinin, cytokines
Increased vascular permeability
Leukocyte chemotaxis
Smooth muscle contraction
Anaphylaxis - eczema, asthma, allergy
Almost always response to a foreign antigen
Rare to see type I auto-reaction - possible involvement of self antigen in some cases of eczema
Type 2 Hypersensitivity
Type II: Antibody reacts with cellular antigen
Antibody binds to cell associated antigen
- Antibody dependent destruction (NK cells, phagocytes, complement)
- Receptor activation or blockade (sometimes considered Type V response)
- Bind to receptor and stimulate = e.g. Graves disease
- Bind to a receptor and bloc = e.g. Myasthaenia gravis – bind acetyl choline receptor
Type 3 Hypersensitivity
Type III: Antibody reacts with soluble antigen to form a circulating immune complex - deposited in blood vessels
Can be self antigens (nuclear – Ab against double stranded DNA/ ribonuclear proteins)
Or foreign proteins – drug reactions – Abs towards e.g. penicillin
Type 4 Hypersensitivity
Type IV: Delayed type hypersensitivity…T-cell mediated response HLA class I molecules present antigen (self peptide) to CD8 T cells HLA class II molecules present antigen (self peptide) to CD4 T cells
Examples of Type 2 Hypersensitivity
Goodpasture disease
Noncollagenous domain of basement membrane collagen type IV = Glomerulonephritis, pulmonary hemorrhage
Pemphigus vulgaris
Epidermal cadherin = Blistering of skin
Graves disease
Thyroid stimulating hormone (TSH) receptor = Hyperthyroidism
Myaesthenia gravis
Acetylcholine receptor = Muscle weakness
Examples of Type 3 Hypersensitivity
Systemic lupus erythematosus - DNA, Histones, RNP
= Rash, glomerulonephritis, arthritis
Rheumatoid arthritis - Fc region of IgG
= Arthritis
Examples of Type 4 Hypersensitivity
Insulin dependent diabetes mellitus
Pancreatic b-cell antigen = b-cell destruction: CD8+ T-cells
Rheumatoid arthritis
Unknown synovial joint antigen = Joint inflammation and destruction
Multiple Sclerosis Experimental autoimmune encephalitis (EAE)
Myelin Basic Protein
Proteolipid protein, Myelin oligodendrocyte glycoprotein = Brain infiltration by CD4+ T-cells,
Graves Disease
AgG Ab stimulates TSH receptor
Type II Hypersensitivity
Hashimotos Thyroiditis
Antithyroid peroxidase Ab
Type II and Type IV Hypersensitivity
T1DM
Antibodies pre-date development of disease
Anti-islet cell antibodies
Anti-insulin antibodies
Anti-GAD antibodies - Glutamic acid dehydrogenase
Anti-IA-2 antibodies - Islet antigen 2
Individuals with 3-4 of the above are highly likely
to develop type I diabetes
Pernicious Anaemia
Anti IF and gastric parietal cell Ab Macrocytic anaemia (failure to absorb Vit B12)
Myasthaenia Gravis
Anti-ACh Receptor Ab
Fluctuating weakness
Extra-ocular weakness or ptosis is very common
EMG studies abnormal
Tensilon test positive
Inject edrophonium (an anti-cholinesterase) to prolong life of acetylcholine and allow it to act on residual receptors)
Offspring of affected mothers may experience
transient neonatal myaesthenia
Type II hypersensitivity reaction
Goodpastures Disease
Anti-basement membrane antibody positive Crescentic nephritis on biopsy Smooth linear deposition of antibody along the glomerular basement membrane Type II hypersensitivity
Rheumatoid Arthritis - genetic predisposition
HLA DR4/ HLA DR1
PTPN 22 polymorphism
Also TNF, IL1, IL6, IL10 polymorphisms
PAD2 and PAD4 polymorphisms
Rheumatoid Arthritis - antibodies
PAD2 and PAD4 = deimination of arginine to citrulline
Polymorphisms a/w increased citrullination
Smoking a/w increased citrullination + development of erosive disease
P gingivalis associated with rheumatoid arthritis
(known to express PAD enzyme)
Anti-CCP Ab (95% specific, 60-70% sensitive)
Anti Rheumatoid Factor (less specific)
Rheumatoid Arthritis - Hypersensitivity
Type II response
Antibody binding to citrullinated proteins may lead to:
Activation of complement
Activation of macrophages via Fc R and complement receptors
NK cell activation with ADCC
Type III response
Immune complex formation (RF and anti-CCP) and deposition with complement activation
Type IV response - T cell activation
