Immunodeficiencies Flashcards
Prevalence
What is immunodefiency and what can it lead to?
- Defects in one or more components of the immune system
- Serious + fatal syndromes/diseases
- Data difficult to estimate
- No current screening programme at birth
Describe the classification of immunodefiencies?
- Primary (congenital) immunodeficiency -> genetic or developmental defect -> Present from birth + mostly inherited -> not clinically observed until later in life
- Secondary immunodeficiency -> Originates via malnutrition, cancer, drug treatment OR infection -> most common is AIDS
Describe clinical features of immunodefiency?
- Recurrent infections, severe infections, unusual pathogens + unusual sites
- Unusual as in they wouldn’t normally cause symptoms within them
Describe the cause of primary immuno-deficency?
- Affects Innate or Adaptive Immune system
- Defects in Innate
- Caused via defect in phagocytic or complement function
- Lymphoid cell disorders affect TOR B cells or both combined ID)
State what components of the immune system targeted lead to PID and what else can it lead to?
- AB
- Cell-mediated immunity
- Complement + phagocytosis
- Can lead to Immunodeficiency + autoimmune disease
Describe how defects during haematopoiesis will affect the consequences?
- Haematopoiesis = formation of blood cellular components via differentiation of stem cells
- Defect -> Depends upon number + type of immune system component involved -> defect in earlier SC - affects entire IS + defect in later SC -> Increase restricted pathology
State what cellular component will be affected via defect causing ID from the colours in this diagram VD
Red= phagocytic
Green= B cell and antibody
Purple= thymic epithelial cell mediated
Blue = combined T and B cell
Primary immunodefiency - Adaptive
Describe the components affected in adaptive immunity in PID?
- B, T cells, both
- T cell defect -> causes AB production impaired -> defect in lymphocyte development or activation (mutation)
What is X-linked agammaglobulinaemia, how does it occur + state clinical symptoms?
- Also Bruton’s disease (X-linked disease)
- Defect in Bruton’s Tyrosine Kinase gene (X chromosome) -> defect in Btk protein -> required for pre-B Cell Receptor signalling -> blocks B-cell development at pre-B stage
- Clinical symptoms: Recurrent severe bacterial infections, 2nd half of first yr (lung, ears, GI) + autoimmune disease (35% of patients)
Describe the diagnosis of X-linked agammaglobulinaemia?
- B cells absent/decrease plasma cells A, all Igs A/V, T-cells + response = normal
- Vla flow cytometry (B + T) + immunoelectorphoresis (Ig)
Describe the treatment for X-linked agammaglobulinaemia?
- URI = upper respiratory infection, LRI = Lower respiratory infection
- IVof Ig: 200-600mg/kg/month at 2-3 wk intervals
- Or subcutaneous Ig weekly
- Prompt antibiotic therapy (URI /LRI)
- Do not give live-attenuated vaccines -> ID -> unable to clear A pathogen
Describe the signs of selective IgA deficiency?
- Asymptomatic cases (sometimes infect resp, uro or GI)
- Increased serum + secretory IgA
- Sometimes increase incidence allergic disease
Describe the causes of severe combined Immunodeficiencies?
- Cytokine receptor v-chain defect (signal transducing component of receptors for many ILs) -> Affects IL-7 - survival T cell precursors -> defective T cell development + concomitant lack in B cell help (low AB)
- RAG-1/RAG-2 defect => noT + B cells
- Adenosine deaminase deficiency -> accumulation of deovadenosine & deoxy-ATP - toxic for thymocytes + die
Describe the characteristics of Severe combined immunodeficiency
- Decrease total lymphocyte count (T,B + NK) = SCID -> Pattern: V/A T; normal/absent B, possible absent NK (v-chain defect affecting IL- 15 receptor),
- Decreased Igs -> Decreased T cell function, proliferation + cytokine
Describe the technique used for diagnosis of SCID?
- Flow cytometry -> B + T cell plots VD
Describe the treatments for SCID?
- Isolation to prevent further infections
- No live vaccines
- Blood products from CMV-negative donors
- IV Ig replacement
- Infection prophylaxis
- Bone marrow/HSC transplant
- Gene therapy (for ADA + y-chain genes)
Describe the outcome of SCID treatment?
- Dependent on promptness of diagnosis
- Survival >80% if early diagnosis, good donor match, no infections pre-transplant
- Survival <40% if late diagnosis, chronic infections, poorly matched donors
- Regular monitoring post BMT -> engraftment
Describe DiGeorge syndrome and explain how it is caused?
- Thymic hypoplasia
- Via 22q11 deletion - Results in failure development of 3+4th pharyngeal pouches - Variable immunodeficiency ( Complete DG - absent thymus OR Incomplete DG - decrease thymus) -> absent or partial T cell development
Describe clinical symptoms of DiGeorge syndrome?
- Dysmorphic face (cleft palate, low-set ears, fish-shaped mouth)
- Hypocalcaemia
- Cardiac abnormalities
Describe Wiskott aldrich syndrome, what is it caused by and its clinical symptoms?
- X-linked
- Defect in WASP (protein involved in actin polymerization -> T cells remodel cytoskeleton for correct signalling) -> progessive ID -> Decrease T cells, decrease T cell proliferation + AB production (V IgM, IgG; † IgE, IgA) -> loss of T cells
- Clinical symptoms: Thrombocytopenia, eczema, infections
Describe the components affected in innate immune system from PID?
- Decrease phagocytes
- altered function + Defects in:
- Phagocyte Recruitment
- Transmigration + complement
What is Chronic Granulomatous Disease caused by and state its main characterisation?
- Mutation in phagocyte oxidase (NADPH) component - required for phagocyte activation (to kill)
- Defective oxidative killing of phagocytosed microbes -> Formation of granulomas on skin
Describe the diagnosis of Chronic Granulomatous Disease?
- Presence of granulomas on skin
- Nitro blue tetrazolium reduction test (~ blue, red majority) + Flow cytometry via dihydrorhodamine assay ->
CGD -> no shift, control shifts (fluorescent in presence of NADPH)
Chediak Higashi Syndrome
Describe the characteristics Chediak Higashi Syndrome?
- Rare genetic disease
- Defect in LYST gene (regulates lysosome traffic)
- Prevents Lysosome binding with phagosome
- Neutrophils have defective phagocytosis
- Repetitive severe infections
Describe the diagnosis of Chediak Higashi Syndrome?
Decreased neutrophils (with giant granules inside)
Describe the mechanisms + presentation of Leukocyte Adhesion Deficiency?
- Mechanisms: Defect in B2-chain integrins (LFA-1, Mac-1), sialyl-Lewis X (selectin ligand), umbilical cord separation (-> diagnosis defect in $2-chain integrins (LFA-1, Mac-1))
- Presentation: Skin, GI tract infections + perianal ulcers
Describe the diagnosis of Leukocyte Adhesion Deficiency?
- Decrease Neutrophil chemotaxis
- Decreased Integrins expression on phagocytes (flow cytometry)
Describe the aims + methods of treating PID?
- Aims: Minimise control infection + Prompt treatment of infection
- Prevention of infection: isolation, antibiotic prophylaxis, vaccination (not live vaccines), Nutrition, Replace defective/absent component of the IS via Bone marrow/SC/thymus + gene therapy
Describe the gene therapy method in PID treatment?
- Bone marrow cells removed
- Separation of immune cell progenitors
- Immune cell progenitors infected with virus to introduce a correct copy of mutated gene
- Cells take up normal gene
- Cells return to patient
- Immune reconstitution
Secondary immunodeficiency (HIV-AIDS
Describe secondary/acquired immunodefiencies stating an example with its treatment?
- Much more common
- Can lead to immunosuppression > e.g. HIV-AIDS -
- Treatment: HAART, PrEP
