UPDATED Immuno: Primary Immune Deficiencies 1

Question 1

What are the four principles of the Immune system ?

Answer 1

• Detect, respond and eliminate pathogens
• Main tolerance to self (protein/microbiome), environmental antigens (food and inhalants) and in pregnancy paternal antigens
• Induce memory (more rapid and greater response) to previously encountered infection/vaccines
• Restore organ/tissue homeostasis (resolution of inflammation, repair injury) after elimination of pathogen

Question 2

Give a brief overview of the 2 immune responses to infection and the exact types

Answer 2

Question 3

Describe the characteristics of the innate immune system (SENSORS)?

Answer 3

• Rapid onset of action
• Germ line receptor to detect conserved molecular structure expressed by different types of micro-organisms
• Pathogen recognition context dependent:
  1. Tissue damage
  2. Effector trained immunity

Question 4

Describe the characteristics of the adaptive immune system?

Answer 4

• Slower onset of action
• Somatic gene re-arrangements of T and B cell receptor which recognize unique micro-organism
• Accessory signals required (co-stimulation molecules/cytokines) to induce T/B cell proliferation and effector function
• Clonal expansion of antigen specific T and B cells and trafficking to site of infection

Question 5

Describe how the Innate and adaptive immune system interact

Answer 5

1. Innate immune system directs adaptive immune responses
2. Adaptive immune system enhances capacity of innate immune system to eliminate infection

Question 6

What detects infection and initiates an immune reponse?

Answer 6

• Epithelial cells
• Tissue macrophages
• Dendritic cells
• Mast cells
• Sensory neurons
• Complement

Question 7

What are the actions of the innate immune reponse?

Answer 7

• Enhance barrier function
• Secrete cytokines, chemokines and interferons
• Activate complement
• Recruit circulating neutrophils & monocytes
• Induce adaptive immune responses in secondary LT
• Internal (phagosome-lysosome formation) & external (cell degranulation) pathogen killing

Question 8

What do denderitic cells do induce distinct cell mediated immune responses?

Answer 8

Question 9

Outline type 1 immune response to intracellular pathogens:

Answer 9

Question 10

Outline type 3 immune response to intracellular pathogens:

Answer 10

Question 11

Outline Type 2 immune response to extracellular parasites

Answer 11

Question 12

What are the four different types of B cell?

Answer 12

Question 13

How are immunoglobulins structured?

Answer 13

2 heavy and light chains

2 functional units:
1. Fab: antigen recognition
2. Fc: effector function

Question 14

What are the 2 functional sub units of immunnoglobulins and what do they do?

Answer 14

Fab subunit:
* Positive selection/glycosylation in LN GC
* Neutralisation of toxins/virulence factor

Fc subunit:
* Isotype Class Switching
* Ig subclasses
* Modification of hinge region
* Glycosylation
* Affinity to Fc receptors

Question 15

What does the Fc region of the immunoglobulin do?

Answer 15

• Antibody Fc region provides the mechanistic linkbetween antigen specific V-domain and 4 main antigen non specific activities.
• Activation of complement (IgM > IgG&raquo_space;> IgA)
• Clearance and elimination of antibody coated pathogens (IgG, IgA)
  
  • Phagocytosis (internal killing) and cytotoxicity ( external killing)
• Transport and delivery of immunoglobulin to different body compartments (IgG and IgA )
• Regulation of immune responses (IgG/IgA)
  
  • B cell activation, DC function, cytokine secretion, ROS production)

Question 16

What are Inborn Errors of Immunity (IEI)?

Answer 16

Heterogeneous group of genetic disorders resulting in immune dysfunction and ill health

Question 17

What has led to an exponential increase in genetic causes of IEI?

Answer 17

DNA sequencing technology

Question 18

Give the epidemiological distribution of the following:
- Antibody deficiency
- Immunodeficiencies affecting cellular and humoral immunity
- Defects in intrinsic and innate immunity
- Congenital defects of phagocyte number/function/both
- Well-defined syndromes with immunodeficiency
- Disease of immune dysregulation
- Complement deficiencies

Answer 18

1. Antibody deficiency
2. Well-defined syndromes with immunodeficiency
3. Complement deficiencies
4. Congenital defects of phagocyte number/function/both
5. Immunodeficiencies affecting cellular and humoral immunity
6. Disease of immune dysregulation
7. Defects in intrinsic and innate immunity

Question 19

Immune deficiencies exhibit what diverse clinical features?

Answer 19

• Susceptibility to infection
• Autoimmune disease
• Allergic disease
• Auto-inflammatory disease
• Viral related (EBV, HPV) cancers

Question 20

what is the risk of a life-threatening disease occuring?

Answer 20

1% risk for 99% of pathogens at any time and in any given region

An infectious agent is necessary but may not be sufficient to cause severe disease or death ( host factors also involved)

Question 21

What are the four phenotypes of Inborn errors of immunity?

Answer 21

Question 22

What makes you genetically susceptible to TB?

Answer 22

• Monogenic genetic mutations in IL-12 receptor and TYK2 associated with TB in children ( very rare)
• P1104A polymorphic variant of TYK2 ( signalling protein involved in generation of Type 1 immune response) associated with increased risk of TB
• P1104A allelic variant found in 4% of European ancestry: P1104A homozygous 1:6000
• Variant impairs IL-23 but not IL-12 signalling
• 80% chance that P1104A will develop TB disease if exposed: account for 1% cases of TB in UK and Europe

Question 23

A genetic mutation in what, makes you more susceptible to COVID-19?

Answer 23

3.5% of critically ill patients with COVID-19 have genetic mutation in type 1 interferon immune pathway

10% of severely ill patients with COVID-19 infection had neutralising antibodies which inhibit type 1 interferon immune responses

90% of patients with neutralising autoimmune interferon antibodies were male

Neutralising absent in patient with mild or asymptomatic disease

No patients had a previous history of severe viral infections

SARS-Cov-2 infection in 2020: 0.6-1.0% mortality and 2-4% critical care illness

Question 24

Describe the relationship between susceptibility to infection and autoimmune/auto-inflammatory disease

Answer 24

• Loss of function in immune related genes: immune deficiency
• Gain of function in immune related gene: autoimmune/auto-inflammatory disease
• Evolutionary trade off between protection from infection and development of autoimmune/auto-inflammatory disease

Question 25

What is a characteristic feature of autoimmune disease?

Answer 25

Presence of pathological self reactive T cell immune responses

Question 26

What do autoimmune diseases result from?

Answer 26

Result from inborn errors of: * T cell tolerance * T cell apoptosis * T regulatory function

Question 27

What are some features of autoimmune diseases?

Answer 27

Hypomorphic (partial loss of function) -> SCID gene defects Present with early onset autoimmune disease -> SLE, ITP, AIHA Difficult to treat autoimmune cytopaenia -> AIHA, ITP

Question 28

What is an autoinflammatory disease?

Answer 28

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

Question 29

What is the clinical presentation of autoinflammatory disease?

Answer 29

Clinical presentation of fever, skin rashes, arthritis and other manifestations of inflammatory disease in the absence of autoimmunity or infection

Question 30

What are the two major categories of monogenic autoinflammatory disorders

Answer 30

1. IL-1 inflammasomopathies (Familial Mediterranean Fever) 2. Type 1 interferonopathies (Aicardi Goutiers Syndrome )

Question 31

What are some allergic disorders, and what can they present with?

Answer 31

Eczema, eosinophilia and elevated IgE can be a manifestation of IEI Present with **severe atopic disease**, **refractory to standard therapy** AND Either **increased susceptibility to infection**, **autoimmune disease**, **skeletal and vascular abnormalities** and **neuro-developmental delay**

Question 32

What are the clinical features of allergic disorders and what are the immune defects?

Answer 32

- Eczema, bacterial (Staph aureus) and fungal (candida albicans) skin and lung infections (Staph aureus) , bone disease and elevated IgE - Immune defect - Failure to of CD4 Th17 development (oral candida): - Defect IL-6 signalling (Staph aureus infection, cutaneous allergic disease, increased IgE)

Question 33

What is the underlying inheritance of allergic disorders?

Answer 33

Autosomal dominant (AD) STAT-3 Loss of Function (LOF)

Question 34

What does EBV cause in immune deficient patients?

Answer 34

Causes Hodgkin’s disease, non-Hodgkin’s lymphoma and smooth muscle cancers

Question 35

What is the immunological basis for IEL related EBV cancers

Answer 35

* Combined immune deficiency syndromes affecting CD8 T cells NK cell * Impairment CD8 and NK cytotoxic function due to deficiency of perforin, or molecule involved in release of cytolytic granules (XLP, XIAP) * Loss/reduction of proximal signalling molecules in T cell and NK activation

Question 36

What are the clinical presentations of IEL?

Answer 36

* Heterogeneous clinical presentation * Minor symptoms : Selective IgA deficiency (IgA < 0.07g/L): 70% * Modest symptoms: Common Variable Immune Deficiency (infection only variant) supported by weekly or monthly IgG therapy * Life threatening: Severe Combined Immune Deficiency unless corrected by BMT and/or gene therapy

Question 37

What is the mneumonic for the presentations of IEL Infections?

Answer 37

* **S**evere (sepsis, need for intravenous/OPAT antibiotics or fungal drugs) * **P**ersistent Multiple course of antibiotics to treat standard bacterial chest or sinus infection * **U**nusual infections Opportunistic organism (Pneumocystis jirovecci, BCG) * **R**ecurrent More than 2 episodes of pneumonia within a year More than 8 episodes of Otitis Media in a child ## Footnote Consider possibility of IEL in conditions arising from complication of recurrent infections (Bronchiectasis and chronic rhino-sinusitis)

Question 38

What are some other clinical presentations of IEL?

Answer 38

* Early onset or refractory autoimmune cytopenias * Very early onset inflammatory disease (IBD), Haemophagocytic Lympohistiocytosis (HLH), unexplained inflammatory skin disease, or granulomatous disease, * Difficult to treat allergic skin disease with systemic features to suggest possibility of IEL ( infection, autoimmune disease etc) * Unexplained viral induced cancers in patient less than 40 year * EBV lymphoproliferative disease * HPV cutaneous warts * Family history of immune deficiency and/or consanguinity

Question 39

What is the first Line blood test for immune deficiency?

Answer 39

**FISH for an immunodeficiency** * **F**ull Blood count * Hb < 10g/L * neutrophil count less than 1.0 x 109/L * lymphocyte count less than 1.0 x 109/L * platelet count < 50 x109/L * **I**mmunoglobulins (IgG, IgA, IgM, IgE ) * **S**erum complement (C3, C4): * **H**IV test (18-80 years) **If tests are abnormal refer to specialist clinical service** Strategy will pick up to 85% of all immune defects

Question 40

What are serum immunoglobulins and why are they useful?

Answer 40

* IgG is key to host defence in tissues: Blood IgG reflect alveolar levels. * Risk of pneumonia increases with IgG level < 4.0g/L * Secretory IgA and IgM protect mucosal surfaces: origin mucosal B cells: blood levels may not reflect mucosal immunity in upper and lower airways

Question 41

What are some second line tests to investigate immune deficiencies?

Answer 41

* Renal and Liver profile (Albumin) * Calcium and bone profile * Serum protein electrophoresis * Serum free light chains * Urine protein/Creatinine ratio Performed in specialist allergy/immunology clinics

Question 42

What are tetanus and pneumovax vaccines made of?

Answer 42

Tetanus toxoid - Protein antigen Pneumovax vaccine - Carbohydrate antigen

Question 43

Why would you measure the concentration of vaccine antibodies?

Answer 43

If vaccine antibody levels are low offer test immunisation with Pneumovax II and tetanus to investigate immune function Failure to respond to vaccination is part of diagnostic criteria for a number of primary antibody deficiency syndromes.

Question 44

What are some third line tests to diagnose immune deficiencies

Answer 44

* Genetic tests : Immune Deficiency Next Generation Sequencing Panels * Assay to assess neutrophil and complement function * Flow cytometry assay to analyse T and B cell subsets (marginal zone and memory B cells: naïve and memory T cell subsets) * Assay to assess T cell function: proliferation and cytokine production * Anti-cytokine antibody assays

Question 45

Give some outlines for genetic testing for IEL:

Answer 45

* Informed consent required in NHS for genetic tests * Advise patient about test outcomes * Mutation: pathology * Polymorphism: benign variant * Variance of unknown significance (VUS) no answer available * Positive test results implications for other family members and future pregnancies * Clarify consent for long term DNA storage, future access for further testing or 3rd party access (research/industry)