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Sophia's Path > Immuno > Flashcards

Immuno Flashcards

1
Q

Clinical Features suggesting immunodeficiency

A

x2 major or x1 major and recurrent minor infections in one year

unusual organisms
unusual sites
unresponsive to tx
chronic infections
early structural damage
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2
Q

Clinical Features suggesting PRIMARY immunodeficiency

A

Family hx
Young age at presentation
Failure to thrive

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3
Q

Reticular Dysgenesis

A 
Severe SCID
Failure of stem cell differentiation (myeloid or lymphoid lineage)
Fatal (BM transplant)
Autosomal recessive
Mutation: AK2
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4
Q

Kostmann Syndrome

A

Severe congenital neutropenia
Specific failure of neutrophil maturation
Autosomal recessive
Mutation: HAX-1

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5
Q

Cyclic Neutropenia

A

Episodic neutropenia (4-6w)
Specific failure of neutrophil maturation
Mutation: ELA-2

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6
Q

Leukocyte adhesion deficiency

A

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

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7
Q

Chronic Granulomatous Disease

A

NADPH oxidase component deficiency
Impaired oxidative killing of pathogens

Granuloma formation
Lymphadenopathy and HSM

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8
Q

Chronic Granulomatous Disease - susceptible pathogens

A

Catalase positive bacteria - PLACESS

Pseudomonas
Listeria
Aspergillus (fungal)
Candida (fungal)
E. Coli
Staph A
Serratia
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9
Q

Chronic Granulomatous Disease - tests and management

A

Presence of hydrogen peroxide
NBT - yellow to blue colour change
DHR - oxidsed to rhodamine (strongly fluorescent)
NEGATIVE

Specific tx - IFNgamma therapy

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10
Q

IL12 (IL12R) and IFNy (IFNyR) Deficiency

A

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

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11
Q

Classical NKC deficiency

A

Absent NKC in peripheral blood

Mutations: GATA2 and MCM4 in subtypes 1 and 2

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12
Q

Functional NKC deficiency

A

Abnormal NKC function

Mutations: FCGR3A in subtypes 1

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13
Q

NKC deficiency - infections

A

Increased risk of viral infections

HSV1 + 2, VZV (recurrent, EBV, CMV, papillomavirus (uncontrolled, multiple infections)

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14
Q

NKC deficiency - treatment

A 
Prophylactic antivirals (acyclovir, gancyclovir)
Cytokine therapy - TNF alpha stimulates cytotoxic function (in functional deficiency)
Stem cell transplant for severe phenotype
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15
Q

Complement Deficiencies (any defect)

A 
Inability to make MAC 
Increased risk of encapsulated bacteria 
Neiserria meningitidis
Strep pneumoniae
Haemophilus influenzae
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16
Q

Classical Complement Pathway Deficiency

C1, C2, C4

A

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

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17
Q

Secondary Classical Complement Pathway Deficiency

A

Persistent production of immune complexes in SLE leads to depletion of classical complement

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18
Q

MBL Deficiency

A

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

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19
Q

C3 Deficiency

A

C3 Deficient - Meningococcus, streptococcus, haemophilus

Increased risk of connective tissue disorder

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20
Q

Secondary C3 Deficiency

A

Nephritic factors act as auto-Ab
Stabilise C3 convertase - C3 activation and consumption

A/w glomerulonephritis (membranoproliferative)
May be a/w partial lypodystrophy

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21
Q

Alternate Pathway Deficiencies

A

Factors B/I/P (Properidin)
unable to rapidly mobilise complement
encapsulated bacteria infections (recurrent)

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22
Q

Testing for Complement Deficiencies

A

CH50 - classical pathway
AP50 - alternative pathway
Both - common pathway

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23
Q

Complement Deficiencies Management

A

Vaccination - against meningococcus (Meningovax), pneumococcus (Pneumovax), Haemophilus (HIB)

Prophylactic abx - usually penicillin
Treat infection aggressively
Screen family members (C7, C9 deficiency)

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24
Q

Hereditary angiodema

A

Decreased C1 inhibitor

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25
Q

SCID

A

<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

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26
Q

X-Linked SCID

A

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

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27
Q

ADA Deficiency SCID

A

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)

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28
Q

CD8+ T cells

A

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

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29
Q

CD4+ T cells

A

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

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30
Q

CD4+ T cell subtypes - Th1

A

Help CD8 T cells and macrophages
Intracellular pathogens
IL-2, IFNy, TNFa, IL-10

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31
Q

CD4+ T cell subtypes - Th17

A

Neutrophil recruitment
Extracullular pathogens
Inflammatory disease
IL-17, IL-21, IL22

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32
Q

CD4+ T cell subtypes - Treg

A

IL-10/ TGF beta expressing
CD25+
Foxp3+

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33
Q

CD4+ T cell subtypes - TFh

A

Follicular helper T cells
B cell response - germinal centre (differentiation into memory/ plasma cells - class switching)
IL-2, IL-10, IL-21

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34
Q

CD4+ T cell subtypes - Th2

A

Helper T cells

Helminth parasite

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35
Q

DiGeorge Mutation

A

Deletion at 22q11.2
TBX1 may be responsible (usually sporadic)
Pharyngeal pouch developmental defect

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36
Q

DiGeorge features

A 
CATCH-22
Cardiac abnormalities (ToF)
Abnormal facies (high forehead, low set ears)
Thymic aplasia (T cell lymphopenia)
Cleftpalate
Hypocalcaemia/hypoPTH
22- chromosome
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37
Q

Bare Lymphocyte Syndrome (BLS) Type 2

A

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

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38
Q

BLS Type I

A

Failure to express MHC Class I

Profound CD8+ deficiency

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39
Q

T Cell Function Disorders

A

Deficiency of IFNy and IL-12 (and their receptors)

40
Q

T-B cell communication disorder

A

Hyper IgM Syndrome

Failure to express CD40L

41
Q

Clinical features of T cell deficiency

A

Viral infections - CMV
Fungal infection - PCP, cryptosporidium
Some bacterial infections (intra-cellular orgnanisms) - TB, Salmonella
Early malignancy

42
Q

Investigations for T cell deficiencies

A

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

43
Q

Treatment for T cell deficiencies

A

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)

44
Q

B cell reactions

A
  1. Early IgM response (T cell independent) - differentiate to produce IgM memory cells, Ab secreting plasma cells
  2. 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
45
Q

Immunoglobulins

A 
IgM = pentamer
IgA = dimer
Heavy chain = class
Fab domain = recognises antigen
Fc domain determines function (bound by complement, phagocytes, natural killer cells)
46
Q

Bruton’s X Linked Hypogammaglobinaemia

A

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

47
Q

Hyper IgM Syndrome

A

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
48
Q

Selective IgA Deficiency

A

1:600
2/3 asymptomatic
1/3 recurrent resp infections (+ GI infections)
unknown cause

49
Q

Common Variable Immune Deficiency definition

A

1, Marked reduction in IgG (also low IgA, IgE)

  1. Poor/ absent response to vaccination
  2. Absence of other defined deficiency

Recurrent bacterial infections with severe end organ damage (bronchiectasis)
AI disease
Granulomatous disease

50
Q

Clincial Features of Ab Deficiency (or CD4 T cell deficiency)

A

bacterial infections - steph, strep
toxins - tetanus, diptheria
some viral infections - enterovirus

51
Q

Muckle Wells Syndrome

Monogenic Auto-inflammatory

A

Gene: NLRP3 - Gain of function

Protein: NALP3

Inheritance: Cryopyrin
Autosomal dominant

52
Q

Familial cold auto-inflammatory syndrome

Monogenic Auto-inflammatory

A

Gene: NLRP3 - Gain of function

Protein: NALP3

Inheritance: Cryopyrin
Autosomal dominant

53
Q

Chronic infantile neurological cutaneous articular syndrome

Monogenic Auto-inflammatory

A

Gene: NLRP3 - Gain of function

Protein: NALP3

Inheritance: Cryopyrin
Autosomal dominant

54
Q

TNF receptor associated periodic syndrome

Monogenic Auto-inflammatory

A

Gene: TNFRSF1

Protein: TNF receptor

Inheritance: Autosomal dominant

55
Q

Hyper IgD with periodic fever syndrome

Monogenic Auto-inflammatory

A

Gene: MK

Protein: Mevalonate kinase

Inheritance: Autosomal recessive

56
Q

Familial mediterranean fever

Monogenic Auto-inflammatory

A

Gene: MEFV

Protie: Pyrin-marenostrin

Inheritence: Autosomal recessive

57
Q

Familial Mediterranean Fever (Pathogenesis)

A

Pyrin-marenostrin expressed mainly in neutrophils

Failure to regulate cryopyrin driven activation of neutrophils

Intermittent episodes of inflammation

58
Q

Familial Mediterranean Fever (Clinical presentation)

A

Periodic fevers lasting 48-96 hours associated with:
Abdominal pain due to peritonitis
Chest pain due to pleurisy and pericarditis
Arthritis
Rash

59
Q

Familial Mediterranean Fever - long term risk

A

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

60
Q

Familial Mediterranean Fever

A

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)

61
Q

APS1/ APECED

A

Autosomal recessive
Defect in ‘auto-immune regulator’ – AIRE
Leads to failure of central tolerance
Autoreactive T and B cells

62
Q

AIRE

A

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)

63
Q

APS1/ APECED - presentation

A 
Multiple auto-immune diseases:
Hypoparathyroidism 	Addisons
Hypothyroidism
Diabetes
Vitiligo
Enteropathy

Antibodies vs IL17 and IL22 = Candidiasis

64
Q

IPEX

A

Mutations in Foxp3 -required for Treg cell development

Fail to negatively regulate T cell responses = autoAb formation

65
Q

IPEX - presentation

A 
Autoimmune diseases
Enteropathy
Diabetes Mellitus
Hypothyroidism 
Dermatitis – eczematous rash with high IgE

Diarrhoea Diabetes Dermatitis

66
Q

ALPS

A

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’

67
Q

ALPS - Presentation

A

++ lymphocyte numbers
large spleen/ LN

Double negative (CD4-CD8-) T cells

Commonly auto-immune cytopenias

Lymphoma – failure to control T cell proliferation

68
Q

Crohns Disease

A

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

69
Q

Crohns Disease - Treatment

A

Corticosteroid
Azathioprine
Anti-TNF alpha antibody
Anti-IL12/23 antibody – more recent anti-IL 23 probably important

70
Q

Ankylosing Spondylitis - genes

A 
IL23R (IL-23 promotes Th17 cell differentiation - secrete IL-17)
ERAP1 (ARTS1)
ANTXR2
ILR2
HLAB27
71
Q

Ankylosing Spondylitis - Presentation

A

Low back pain and stiffness
Large joint arthritis
Enthesitis
Uveitis

72
Q

Ankylosing Spondylitis -Treatment

A

Non-steroidal anti-inflammatory drugs
Immunosuppression – block TNF alpha pathway
Anti-TNF alpha
Anti-IL17 – recent (see mutations IL23R)
Anti-IL12/23

73
Q

Goodpastures HLA

A

HLA-DR15

74
Q

Graves Disease HLA

A

HLA-DR3

75
Q

SLE HLA

A

HLA-DR3

76
Q

T1DM HLA

A

HLA-DR3/4

77
Q

RA HLA

A

HLA-DR4

78
Q

PTPN22

A

Suppresses T cell activation

Mutations in SLE, T1DM, RA

79
Q

CTLA4

A

Regulates T cell activation

Mutations in SLE, T1DM, Autoimmune Thyroid Disease, (RA)

80
Q

Type I Hypersensitivity

A

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

81
Q

Type 2 Hypersensitivity

A

Type II: Antibody reacts with cellular antigen
Antibody binds to cell associated antigen

  1. Antibody dependent destruction (NK cells, phagocytes, complement)
  2. 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
82
Q

Type 3 Hypersensitivity

A

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

83
Q

Type 4 Hypersensitivity

A 
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
84
Q

Examples of Type 2 Hypersensitivity

A

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

85
Q

Examples of Type 3 Hypersensitivity

A

Systemic lupus erythematosus - DNA, Histones, RNP
= Rash, glomerulonephritis, arthritis

Rheumatoid arthritis - Fc region of IgG
= Arthritis

86
Q

Examples of Type 4 Hypersensitivity

A

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,

87
Q

Graves Disease

A

AgG Ab stimulates TSH receptor

Type II Hypersensitivity

88
Q

Hashimotos Thyroiditis

A

Antithyroid peroxidase Ab

Type II and Type IV Hypersensitivity

89
Q

T1DM

A

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

90
Q

Pernicious Anaemia

A 
Anti IF and gastric parietal cell Ab
Macrocytic anaemia (failure to absorb Vit B12)
91
Q

Myasthaenia Gravis

A

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

92
Q

Goodpastures Disease

A 
Anti-basement membrane antibody positive
Crescentic nephritis on biopsy
Smooth linear deposition of antibody along 
the glomerular basement membrane
Type II hypersensitivity
93
Q

Rheumatoid Arthritis - genetic predisposition

A

HLA DR4/ HLA DR1
PTPN 22 polymorphism
Also TNF, IL1, IL6, IL10 polymorphisms
PAD2 and PAD4 polymorphisms

94
Q

Rheumatoid Arthritis - antibodies

A

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)

95
Q

Rheumatoid Arthritis - Hypersensitivity

A

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

Sophia's Path (8 decks)

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