UPDATED Immuno: Primary Immune Deficiencies 1 Flashcards
What are the four principles of the Immune system ?
- 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
Give a brief overview of the 2 immune responses to infection and the exact types
Describe the characteristics of the innate immune system (SENSORS)?
- 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
Describe the characteristics of the adaptive immune system?
- 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
Describe how the Innate and adaptive immune system interact
- Innate immune system directs adaptive immune responses
- Adaptive immune system enhances capacity of innate immune system to eliminate infection
What detects infection and initiates an immune reponse?
- Epithelial cells
- Tissue macrophages
- Dendritic cells
- Mast cells
- Sensory neurons
- Complement
What are the actions of the innate immune reponse?
- 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
What do denderitic cells do induce distinct cell mediated immune responses?
Outline type 1 immune response to intracellular pathogens:
Outline type 3 immune response to intracellular pathogens:
Outline Type 2 immune response to extracellular parasites
What are the four different types of B cell?
How are immunoglobulins structured?
2 heavy and light chains
2 functional units:
1. Fab: antigen recognition
2. Fc: effector function
What are the 2 functional sub units of immunnoglobulins and what do they do?
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
What does the Fc region of the immunoglobulin do?
- Antibody Fc region provides the mechanistic linkbetween antigen specific V-domain and 4 main antigen non specific activities.
- Activation of complement (IgM > IgG»_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)
What are Inborn Errors of Immunity (IEI)?
Heterogeneous group of genetic disorders resulting in immune dysfunction and ill health
What has led to an exponential increase in genetic causes of IEI?
DNA sequencing technology
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
- Antibody deficiency
- Well-defined syndromes with immunodeficiency
- Complement deficiencies
- Congenital defects of phagocyte number/function/both
- Immunodeficiencies affecting cellular and humoral immunity
- Disease of immune dysregulation
- Defects in intrinsic and innate immunity
Immune deficiencies exhibit what diverse clinical features?
- Susceptibility to infection
- Autoimmune disease
- Allergic disease
- Auto-inflammatory disease
- Viral related (EBV, HPV) cancers
what is the risk of a life-threatening disease occuring?
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)
What are the four phenotypes of Inborn errors of immunity?
What makes you genetically susceptible to TB?
- 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
A genetic mutation in what, makes you more susceptible to COVID-19?
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
Describe the relationship between susceptibility to infection and autoimmune/auto-inflammatory disease
- 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
What is a characteristic feature of autoimmune disease?
Presence of pathological self reactive T cell immune responses
What do autoimmune diseases result from?
Result from inborn errors of:
* T cell tolerance
* T cell apoptosis
* T regulatory function
What are some features of autoimmune diseases?
Hypomorphic (partial loss of function) -> SCID gene defects
Present with early onset autoimmune disease -> SLE, ITP, AIHA
Difficult to treat autoimmune cytopaenia -> AIHA, ITP
What is an autoinflammatory disease?
Aberrant activation of innate inflammatory pathways in the absence of antigen directed autoimmunity
What is the clinical presentation of autoinflammatory disease?
Clinical presentation of fever, skin rashes, arthritis and other manifestations of inflammatory disease in the absence of autoimmunity or infection
What are the two major categories of monogenic autoinflammatory disorders
- IL-1 inflammasomopathies (Familial Mediterranean Fever)
- Type 1 interferonopathies (Aicardi Goutiers Syndrome )
What are some allergic disorders, and what can they present with?
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
What are the clinical features of allergic disorders and what are the immune defects?
- 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)
What is the underlying inheritance of allergic disorders?
Autosomal dominant (AD) STAT-3 Loss of Function (LOF)
What does EBV cause in immune deficient patients?
Causes Hodgkin’s disease, non-Hodgkin’s lymphoma and smooth muscle cancers
What is the immunological basis for IEL related EBV cancers
- 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
What are the clinical presentations of IEL?
- 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
What is the mneumonic for the presentations of IEL Infections?
- 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)
What are some other clinical presentations of IEL?
- 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
What is the first Line blood test for immune deficiency?
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
What are serum immunoglobulins and why are they useful?
- 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
What are some second line tests to investigate immune deficiencies?
- 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
What are tetanus and pneumovax vaccines made of?
Tetanus toxoid - Protein antigen
Pneumovax vaccine - Carbohydrate antigen
Why would you measure the concentration of vaccine antibodies?
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.
What are some third line tests to diagnose immune deficiencies
- 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
Give some outlines for genetic testing for IEL:
- 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)
