Imm - Immune deficiencies

Question 1

What are the two pathways for pathogen detection

Answer 1

Microbial PMP → recognition of structure → Th1 and Th17 immune response

Toxins/helminths → detection of loss of function → Th2 immune response

Question 2

Describe the innate immune response

Answer 2

Direct clearance of pathogens and/or innate immune cell activation

Virus/bacteria/fungus is detected by sensor cells →
- Type 1 and 3 interferon production
- Recruitment of circulating neutrophils and monocytes
- Effector activity: phagocytosis and release of mast cell granules

Question 3

What cells act as sensors in the innate immune response

Answer 3

Epithelial cells
Dendritic cells
Macrophages
Mast cells

Question 4

Describe the adaptive immune response

Answer 4

Response with specificity for the pathogen and development of long term memory

1. Virus/bacteria/fungus activate dendritic cell subsets
2. • Cytokine production
   • Type 1 interferon, IL-6, IL-12, IL-23, TGF-beta release
   • CD4 and functional T helper cell
3. Lymphocyte release (Cytotoxic T cell, CD4+Th1, CD4+Th17, GC+B cell)

Question 5

What is the role of CD4 and Th1 in the adaptive immune system

Answer 5

Release cytokines IFNy, TNF-a, IL-2 → macrophage and CTL activation

Question 6

What is the role of CD4, Th17 in the adaptive immune response

Answer 6

Release of cytokines IL-17A and IL-22 → Neutrophil and epithelial cell activation

Question 7

What is the role of CD4 and TFh in the adaptive immune response

Answer 7

Release of cytokines IFN-y, IL-17A, IL-4, IL-21 → GC B cells, memory B cells/plasma cells → IgG, IgA, IgE and CTL

Question 8

Describe the structure of immunoglobulins

Answer 8

2 soluble heavy and light chains
Each contains 2 distinct regions:
Fab: fragment antigen binding
Fc: determines effector functions

The heavy chain specifies the antibody isotype (IgG/A/E/M/D)

Question 9

What does IgG FcR binding activated

Answer 9

Activation of complement
Clearance and elimination of antibody coated pathogens
Opsonisation, phagocytosis, mast cell degranulation
Transport and delivery of immunoglobulins to different compartments
Regulation of immune response
B cell activation

Question 10

What is the most common overall (cellular) cause of inborn errors of immunity (IEI)

Answer 10

Antibody deficiency (B cells)

Question 11

What are the causes of inborn errors of immunity

Answer 11

Antibody deficiency
Complement deficiency
Well-define syndromes
Congenital defects of phagocyte number or function
Immunodeficiency affecting cellular and humoral immunity
Disease of immune dysregulation
Defects in intrinsic and innate immunity

Question 12

What are the overall clinical features of immune deficiencies

Answer 12

Susceptibility to infection
Autoimmune disease
Allergic disease
Auto-inflammatory disease
Viral related cancers

Question 13

Describe primary immune deficiencies / syndromic infectious diseases (age groups, penetrance, cells affected, inheritance)

Answer 13

A susceptibility to multiple infections and a large number of infectious episodes
Often rare, opportunistic infections
Children > adults
High or complete penetrance
Leukocytes affected
Inheritance: X-linked and autosomal recessive

Question 14

Give examples of primary immune deficiencies

Answer 14

Severe combined immunodeficiency (SCID)
X-linked A-gamma-globulinaemia (XLA)
Chronic granulomatous disease (CGD)

Question 15

Describe familial infectious disease (age groups, penetrance, cells affected, inheritance)

Answer 15

Susceptibility to single/few infections with single or multiple infectious episodes
Children > adults
High or complete penetrance
Leukocytes and epithelial cells
Inheritance: X-linked, autosomal recessive, autosomal dominant

Question 16

Give examples of familial infectious diseases

Answer 16

Mendelian susceptibility to mycobacterial disease
Critical Influenzae pneumonia

Question 17

What is the pathophysiology of Mendelian susceptibility to Mycobacterial infection

Answer 17

Gene defects in generation and responses to IFN-y
- Generation: IL-12 and IL-23
- Response: IFN-yR and Tyk2
The infected macrophages produce IL-12/IL23 → induces T cells to IFN-γ → Acts on macrophages and neutrophils → stimulates TNF-a and NADPH oxidase to eliminate the pathogen

High residual IFn-y activity + variable penetrance

Question 18

What si the pathophysiology of critical influenza pneumonia

Answer 18

Toll-like-receptor (TLR) 3 recognises influenza virus infection → type 1 interferon production → promotion of expression of interferon stimulated genes (ISG) → induces antiviral state in neighbouring cells

Question 19

Describe susceptibility to sporadic infectious disease

Answer 19

Susceptibility to one infectious agent with single episode of infection
Seen in children or adults
Low penetrance
Cells: leukocytes, epithelial cells, neurones
Inheritance: X-linked, autosomal recessive, autosomal dominant

Question 20

Give examples of susceptibility to sporadic infectious disease

Answer 20

Critical illness from influenza pneumonia
Invasive neisseria disease

Question 21

What gene variant increases risk of TB

Answer 21

P1004A of the TYK2 → 80% chance of developing T
Impairs IL-23 (but not IL-12)

Question 22

What gene variant is seen in patients with severe COVID-19 infection

Answer 22

Defect in type 1 interferon immune pathway
10% of severely ill patients had neutralising antibodies that inhibit type 1 interferon response

Question 23

What are the inborn errors of autoimmune disease

Answer 23

Characteristic: self-reactive T cell immune response

Errors of:
T cell tolerance
T cell apoptosis
T regulatory function

Question 24

Give examples of autoimmune disease from inborn errors of immunity

Answer 24

SCID
SLE
ITP
AIHA

Question 25

What are autoinflammatory responses

Answer 25

Aberrant activation of innate inflammatory pathways in the absence of antigen directed autoimmunity

Question 26

Give examples of autoinflammatory disorders due to inborn errors of immunity

Answer 26

Familial mediterannean fever (IL-1 inflammasomopathies)
Aicardi-Goutiers syndrome (type 1 interferonopathies)

Question 27

What is the main cause of allergic disorders via inborn errors of immunity

Answer 27

Autosomal dominant STAT-3 loss of function → failure of CD4 Th17 development and IL-6 signalling
CD4: fungal infection
IL-6: eczema, bacterial and skin infection, elevated IgE

Question 28

What are the inborn errors of immunity in haematological malignancies

Answer 28

Combined immune deficiency
]Impairment of function due to deficiency of perforin
Loss/reduction of proximal signalling molecules for T cell activation and expression of NKG2D on NK and CD8 T cells

Question 29

What is the presentation of inborn errors of immunity

Answer 29

Severe infection
Persistent infection
unusual pathogens
Recurrent
Complications of recurrent infections e.g. bronchiectasis

Question 30

What are the most common causes of IEL according to severity of symptoms

Answer 30

Asymptomatic/minor symptom: Selective IgA deficiency (IGA <0.07g/L) (most common)

Normal life expectancy: Common variable immune deficiency, supported by weekly/monthly IgG therapy

Life threatening: Severe combined immune deficiency unless corrected by BMT and/or gene therapy

Question 31

What investigations should be done for immunodeficiency

Answer 31

FISH
FBC (neutrophils, lymphocytes, platelets)
Immunoglobulins (IgA, IgG, IgM, IgE)
Serum complement (C3, C4)
HIV testing (18-80years)

± Renal screen | LFTs | calcium and bone profile
| protein and albumin | serum free light chains

Question 32

What is the role of IgG and IgA in the lungs

Answer 32

IgG is key to host defence in alveoli: in equilibrium with blood
Secretory IgA and IgM protect in upper and lower airways
Secretory IgA and IgM originate from mucosal B cells rather then blood

Question 33

What is the second line investigation for immune deficiencies

Answer 33

Measure the concentration of vaccine antibodies e.g. tetanus toxoid and pneumovax

Question 34

Describe genetic testing for immune deficiencies

Answer 34

Sanger sequencing used to confirm mutation
Targeted gene panel sequencing