Primary Immune Deficiencies 1

Question 1

4 Principles of the immune system

Answer 1

1. Detect, respond and eliminate pathogens
2. Maintain tolerance to self antigens, environmental antigens and in pregnancy to paternal antigens
3. Induce memory (rapid greater response) to previously encountered infections
4. Restore organ/tissue homeostasis

Question 2

2 broad responses of the immune system in response to a pathogen

Answer 2

1. Innate immune responses
2. Adaptive immune responses

Question 3

Outline the cells which form part of the innate immune response

Answer 3

Epithelial cells
Granulocytes
Mast cells
Tissue macrophages
Sensory Neurons
Complement
Dendritic cells

Question 4

Outline the actions of the innate immune response

Answer 4

• Barrier function
• Secrete cytokines, chemokines and interferons
• activate complement response
• Recruit circulating neutrophils and monocytes for internal (phagosome-lysosome formation) and external (cell degranualtion) pathogen killing
• Induce adaptive immune responses in secondary Lymphoid Tissue (dendritic cell phagocytoses pathogen > become mature and move to secondary LT > present antigens to prime lymphocytes)

Question 5

What cell delineates the transition of the innate to adaptive immune response and outline the 2 ways it impacts the adaptive immune response

Answer 5

Dendritic Cell

• Present processed antigen via MHC II to CD4 T-cells in lymph nodes to prime the adaptive immune response
• Express cytokines to attract specific type of CD4 T cell and therefore the type of adaptive immune response. The cytokines which they express varies depending on the signal of the pathogen classe their Pathogen-Recognition Receptors and Danger receptors pick up.

Question 6

Briefly outline the different typess of adaptive immune responses to infection

Answer 6

Type 1 = against intracellular pathogens

Type 2 = against extracellular parasites

**Type 3 **= against extracellular bacteria and fungi

Question 7

Describe the pathway of type 1 immune response

include: main immune cell and cytokine

Answer 7

Main immune cell = CD4 Th1 Cell
Main cytokine = IFN gamma

(right side of diagram = in lymph nodes)

Question 8

Describe the pathway of type 2 immune response

include: main immune cell and cytokine

Answer 8

main immune cell = CD4 Th2 Cell main cytokines = IL-5 (and 4 +13)

Question 9

Describe the pathway of type 3 immune response

include: main immune cell and cytokine

Answer 9

main immune cell = CD4 Th17 main cytokine = IL-17

Question 10

Outline the 4 main types of B Cells

Answer 10

Innate-like B cell
* spontaneous production of IgM

Marginal Zone B Cell
* T-Cell independent immune responses - hence do not need to T-cell activation to begin producting antibodies
* Located outside germinal centres in lymphoid organs (commonly found in spleen and GI tissue)
* Protection against encapsulated organisms (commonly carbohydrate - e.g. pneumococcus)
* Produce IgM then IgA then IgG
* Have limited memory and antibody affinity
* Those that have had splenectomy and therefore lack Marginal Zone B Cells are at higher risk of overwhelming infection of encapsulated organisms

Extra-Follicular B Cells
* Respond to proteins (e.g. antigens)
* T-cell dependent and independent
* Rapid response (24-96 hours)
* Can undergo class switching of immunoglobulins (low affinity)
* Produce short lived plasma cells (memory - e.g. sars-COV2 response is by extra-follicular b cells and hence why ppl need booster vaccines as memory is short-lived)

Germinal Centre B Cells
* Respond to proteins (e.g. antigens)
* T-cell dependent activation
* 5-7 days (slower-onset of action)
* Undergo class switching
* Memory - long-term as gives rise to long-lived plasma cells
* High affinity antibodies

Question 11

Outline the structure of immunoglobulins

Answer 11

2 heavy chains + 2 light chains

2 functional units:
* Fab (fragment-antigen binding) unit - binds to specific antigen
* Fc (constant fragment) unit - undergoes class switching and therefore depending on Ig class there is a different immune response.

Question 12

Function of the different classes of immunoglobulins

Answer 12

IgM
* antibody produced in primary response
* less affinity
* important to activate complement immune action

IgG
* Most abundant class - has 4 isotypes
* Neutralises pathogen by opsonization (allows phagocytes to phagocytose pathogen where before they evaded phagocytosis)

IgE
* Defence against parasite infections
* Associated with hypersensitivity
* Activation of mast cells and basophils

IgA
* predominantly found in secretions and mucosa
* binds to bacteria neutralising it (by binding to it, it prevents bacteria to invade through epithelium and adhere to cells to cause damage and also allows easier for phagocytosis and excretion)

IgD
* action not yet known

Question 13

Define inborn errors of immunity (IEL)

Answer 13

Heterogenous group of genetic disorders resulting in immune dysfunction

Question 14

What type of mutations cause IELs

Answer 14

Single gene mutations - approximately 500 single gene mutations have been identified.

Question 15

What are the commonest IELs

Answer 15

Antibody deficiency (hence cellular component behind most IELs is B cell)

B and T cell dysfunction

Complement deficiencies

Question 16

Concequences of IELs

Answer 16

• Increased susceptibility to infection
• Autoimmune disease (e.g. SCID or very early onset of other autoimmune diseases)
• Allergic disease
• Auto-inflammatory disease
• Increased risk of viral related cancers (EBV, HPV)

Question 17

Tell-tale signs of patients with underlying IELs

Answer 17

Infections: SPUR
- Severe (resulting in sepsis)
- Persistent (multple course of abx required to treat chest infecitons etc)
- Unusual (opportunisitc organisms e.g. pneumocystitis jjrovecci)
- Recurrent (more than 2 epsiodes of pneumonia in 1 year or 8 epsidoes of otitis media in a child)

Early onset or resistant autoimmune cytopenias

Very early onset inflammatory disease (IBD, inflammatory skin disease)

Difficult to treat allergic skin disease with systemic features to suggest IEL (recurrent infections, autoimmune disease)

Unexplained viral induced cancers in patients less than 40 years

Family history of immune deficiency or consanguinity

note that not all exisit simultaneously!

Question 18

Describe the phenotype of infections patients with IELs are at risk of

Answer 18

Patients with IELs exhibit a highly variable infection phenotype. They can present with either:

1. Having multiple episodes involving a wide range of infections (common organisms as well as rare opportunistic infections, infections following live vaccines). More common in children
2. Susceptibility to weakly virulent organsims only (environmental TB species or BCG vaccine)
3. Highly susceptibility to single organims only infections (e.g. invasinve Neisseria in complement pathway defects or HSV in neuronal defects)

Question 19

What are the differences between autoinflammatory and autoimmune disorders

Answer 19

Autoinflammatory: hyperactivation of the innate immune system

Autoimmune: abnormalities of the adaptive immune system

Question 20

Why do autoimmune disease arise from IELs

Answer 20

Autoimmune diseases arise from IELs as a result of inborn errors of:
* T cell tolerance
* T cell apoptosis
* T regulatory function

Therefore resul in presence of pathological self reactive T cell immune responses

Question 21

Describe the autoimmune disease phenotype in patients with IELs

Answer 21

• SCID or Hypomorphic SCID
• Early onset autoimmune disease (SLE, ITP, AIHA) - note that childhood onset of these diseases is indiciative of IELs!
• Difficult to treat autoimmune cytopaenia

Question 22

Why do autoinflammatory disease arise from IELs

Answer 22

Due to aberrant activation of innate inflammatory pathways in the absence of antigen directed autoimmunity

Question 23

Describe the autoinflammatory disease phenotype in patients with IELs

Answer 23

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

2 main categories of monogenic (single gene) autoinflammatory disorders:
* IL-1inflammasomopathies (Familial Mediterranaen fever)
* Type 1 Interferonopathies (Aicardi Goutiers Syndrome)

Question 24

What are the immune defect that results in allergic disorders in patients with IELs

Answer 24

• Failure of CD4 Th17 development (oral candida)
• Defect IL-6 signalling (staph a infeciton, cutaneous allergic disease, increased IgE)

Question 25

Describe the allergic disease phenotype in patients with IELs

Answer 25

Present with severe atopic disease, refractory to standard therapy (eczema, eosinophilia, elevated IgE)
AND
Increased suceptibility to infection, autoimmune disease, skeletal and vascular abmormalities or neuro-developmental delay

Question 26

What are the immune defect that result in viral related cancers in IEL patients

Answer 26

Combined immuned deficiency syndromes affecting CD8 T-cells and NK cells:
* deficiency of perforin or molecule (XLP, XIAP) involved in release of cytolytic granules
* loss/reduction of proximal signalling molecules in T cell and NK activation

Question 27

Outline the different severities in clinical presentations of patients with IEL

Answer 27

note! IEL has a hetergenous clinical presentation

Minor symptoms: selective IgA deficiency (IgA<0-07g/L)

Modest symptoms: Common variable immune deficinecy (infection only variant) supported by weekly or monthly IgG therapy

Life threatening: severe combined immune deficency (SCID) unless corrected by bone marrow transplant or gene therapy