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[EDITED] YEAR 5: Immunopathology PM > UPDATED Immuno: Primary Immune Deficiencies 1 > Flashcards

UPDATED Immuno: Primary Immune Deficiencies 1 Flashcards

1
Q

What are the four principles of the Immune system ?

A
  • 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
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2
Q

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

A
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3
Q

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

A
  • 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
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4
Q

Describe the characteristics of the adaptive immune system?

A
  • 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
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5
Q

Describe how the Innate and adaptive immune system interact

A
  1. Innate immune system directs adaptive immune responses
  2. Adaptive immune system enhances capacity of innate immune system to eliminate infection
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6
Q

What detects infection and initiates an immune reponse?

A
  • Epithelial cells
  • Tissue macrophages
  • Dendritic cells
  • Mast cells
  • Sensory neurons
  • Complement
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7
Q

What are the actions of the innate immune reponse?

A
  • 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
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8
Q

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

A
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9
Q

Outline type 1 immune response to intracellular pathogens:

A
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10
Q

Outline type 3 immune response to intracellular pathogens:

A
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11
Q

Outline Type 2 immune response to extracellular parasites

A
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12
Q

What are the four different types of B cell?

A
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13
Q

How are immunoglobulins structured?

A

2 heavy and light chains

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

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14
Q

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

A

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

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15
Q

What does the Fc region of the immunoglobulin do?

A
  • 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)
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16
Q

What are Inborn Errors of Immunity (IEI)?

A

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

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17
Q

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

A

DNA sequencing technology

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18
Q

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

A
  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
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19
Q

Immune deficiencies exhibit what diverse clinical features?

A
  • Susceptibility to infection
  • Autoimmune disease
  • Allergic disease
  • Auto-inflammatory disease
  • Viral related (EBV, HPV) cancers
20
Q

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

A

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)

21
Q

What are the four phenotypes of Inborn errors of immunity?

A
22
Q

What makes you genetically susceptible to TB?

A
  • 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
23
Q

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

A

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

24
Q

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

A
  • 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
25
Q

What is a characteristic feature of autoimmune disease?

A

Presence of pathological self reactive T cell immune responses

26
Q

What do autoimmune diseases result from?

A

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

27
Q

What are some features of autoimmune diseases?

A

Hypomorphic (partial loss of function) -> SCID gene defects

Present with early onset autoimmune disease -> SLE, ITP, AIHA

Difficult to treat autoimmune cytopaenia -> AIHA, ITP

28
Q

What is an autoinflammatory disease?

A

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

29
Q

What is the clinical presentation of autoinflammatory disease?

A

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

30
Q

What are the two major categories of monogenic autoinflammatory disorders

A
  1. IL-1 inflammasomopathies (Familial Mediterranean Fever)
  2. Type 1 interferonopathies (Aicardi Goutiers Syndrome )
31
Q

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

A

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

32
Q

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

A
  • 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)
33
Q

What is the underlying inheritance of allergic disorders?

A

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

34
Q

What does EBV cause in immune deficient patients?

A

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

35
Q

What is the immunological basis for IEL related EBV cancers

A
  • 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
36
Q

What are the clinical presentations of IEL?

A
  • 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
37
Q

What is the mneumonic for the presentations of IEL Infections?

A
  • Severe (sepsis, need for intravenous/OPAT antibiotics or fungal drugs)
  • Persistent
    Multiple course of antibiotics to treat standard bacterial chest or sinus infection
  • Unusual infections
    Opportunistic organism (Pneumocystis jirovecci, BCG)
  • Recurrent
    More than 2 episodes of pneumonia within a year
    More than 8 episodes of Otitis Media in a child

Consider possibility of IEL in conditions arising from complication of recurrent infections (Bronchiectasis and chronic rhino-sinusitis)

38
Q

What are some other clinical presentations of IEL?

A
  • 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
39
Q

What is the first Line blood test for immune deficiency?

A

FISH for an immunodeficiency

  • Full 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
  • Immunoglobulins (IgG, IgA, IgM, IgE )
  • Serum complement (C3, C4):
  • HIV test (18-80 years)

If tests are abnormal refer to specialist clinical service

Strategy will pick up to 85% of all immune defects

40
Q

What are serum immunoglobulins and why are they useful?

A
  • 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
41
Q

What are some second line tests to investigate immune deficiencies?

A
  • 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

42
Q

What are tetanus and pneumovax vaccines made of?

A

Tetanus toxoid - Protein antigen
Pneumovax vaccine - Carbohydrate antigen

43
Q

Why would you measure the concentration of vaccine antibodies?

A

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.

44
Q

What are some third line tests to diagnose immune deficiencies

A
  • 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
45
Q

Give some outlines for genetic testing for IEL:

A
  • 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)

[EDITED] YEAR 5: Immunopathology PM (12 decks)

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