Immunodeficiencies Flashcards
How is immunodeficiency classified?
Primary (congenital)
- defect in immune system
Secondary (acquired)
- caused by another disease
What are the clinical features of immunodeficiencies
- Recurrent infections
- Severe infections, unusual pathogens (Aspergillus, Pneumocystis), unusual sites (liver abscess, osteomyelitis). - An immunocompetent patient is not infected by these pathogens
Outline the warning signs of Primary immunodeficiency
- Recurrent infections, esp. frequent thrush/fungal infections(= unusual)
- Require ↑ antibiotics
What is the main cause of PID?
Usually genetic
- Infrequent but can be life-threatening
What does Primary immunodeficiency (PID) usually cause?
Innate immune system lacks; Phagocytes, Complement
Adaptive immune system defects: T-cells, B cells.
How are defects in adaptive immunity classified?
Sub-classification: primary component affected e.g.
- B cells
- T cells
- Combined (both B & T) = SCID
What cellular defects occur in adaptive immunity during primary immunodeficiency?
T cell defects impair antibody production
Defects in lymphocyte development or activation
Counterintuitively, a patient with an immunodeficiency could simultaneously present with ……..
Autoimmunity
Immunodeficient = lacking an element of immunity
+
Autoimmunity = Damage body’s own tissues bc the immune defect also affects elements of the immune system that regulate other immune cells
Defects in earlier stem cells affect ……
Defects at a later stage lead to a more …………. pathology
-the entire immune system - e.g. defects in HSCs/common lymphoid progenitor/common myeloid progenitor
= affects many immune cells
-restricted - e.g. mature T-cells/mature B-cells/plasma cells - e.g. 1 particular T-cell/B-cell
Name the major B-lymphocyte immunodeficiency disorders
- X-linked agammaglobulinemia (Bruton’s disease)
- Common variable immunodeficiency (CVID)
- Selective IgA deficiency
- IgG2 subclass deficiency
- Specific Ig deficiency with normal Igs
What is the first described immunodeficiency?
X-linked Agammaglobulinemia
What causes Bruton’s disease (agammaglobulinemia) ?
Defect in BTK gene (X chromosome)
BTK gene encodes Bruton’s tyrosine kinase
What is the role of the btk gene?
Encodes Bruton’s tyrosine kinase
What is the effect of BTK gene defect?
BTK needed for pre-B cell receptor signalling
BTK defect blocks B-cell development (stop at pre-B cells)
What is the consequence of Bruton’s disease?
- Recurrent severe bacterial infections
- Autoimmune diseases
What inheritance pattern does agammaglobulinaemia follow?
Agammaglobulinaemia = X-linked
Carrier mother + unaffected father = affected male offspring
What happens to B-cell at Pro-B stage?
Pro-B cell rearranges its Ig(BCR)
At Pre-B stage, B-cell now presents a pre-BCR on its surface
Pre-B cell requires …… downstream in order to continue development
BTK signal
Missing in agammaglobulinaemia = no subsequent B-cell development = patients lack B-cell + Ab production
How do we diagnose Brutons disease (agammaglobulinaemia)?
- B cells absent / low; Plasma cells absent
- All Igs absent / v. low
- T cells + T cell-mediated responses normal
agammaglobulinaemia = B-cell restricted immunodeficiency
How is brutons disease (agammaglobulinaemia) treated?
- IV Ig/Subcutaneous Ig
- Prompt antibiotic therapy (URI /LRI)
- Do not give live vaccines bc cannot clear the pathogen
What is SCID?
Severe Combined ImmunoDeficiency (SCID)
A form of Combined immunodeficiencies
Outline the predominant T cell disorders
- DiGeorge syndrome
- Wiskott-Aldrich syndrome
- Ataxia-telangiectasia
Which lymphocyte disorder is SCID a form of?
- involves both T and B
- 50-60% X-linked; rest - autosomal recessive
Describe the presentation of SCID
- well at birth; problems > 1st month
- diarrhoea; weight loss; persistent candidiasis
- severe bacterial/viral infections
- failure to clear vaccines
- unusual infections (Pneumocystis, CMV)
What are the different causes of SCID?
Different causes; affect T & B cell development e.g:
- Cytokine receptor defects
- RAG defects
- Adenosine Deaminase Deficiency
How do cytokine receptor defects effect T and B cell development?
Common cytokine receptor γ-chain defect
(signal transducing component of receptors for IL-2, 4, 7, 9, 11, 15, 21)
IL-7 needed for survival T cell precursors => defective T cell development => lack in B cell help (low Ab)
What is the effect of RAG enzyme defects?
RAG-1/RAG-2 defect => no T and B cells
RAG enzymes are involved in TCR + BCR rearrangement
RAG defect = no T-cells/B-cells
RAG enzymes are involved in ………
TCR + BCR rearrangement
RAG defect = no T-cells/B-cells
What is the effect of ADA deficiency?
ADA deficiency = deoxyadenosine & deoxy-ATP accumulate = toxic for rapidly dividing thymocytes
How is SCID investigated?
Lymphocyte subsets
- T, B, NK (% and numbers)
=> low total lymphocyte count
Pattern:
- T v.low/absent
- B normal/absent
sometimes NK also absent (γ-chain defect affecting IL-15 receptor)
- Igs low
- T cell function ↓ (proliferation, cytokines)
How is SCID treated?
- Isolation
- Do not give live vaccines !
- Blood products from CMV -ve donors
- IV Ig replacement
- Treat infections
- Bone marrow/HSC Transplant - replenish BM with precursors w/o the mutation
- Gene therapy (for ADA and γ-chain genes)
Describe SCID prognosis and survival is dependent on ………….
Dependent on promptness of diagnosis
What is DiGeorge syndrome?
Complex array of developmental defects
Affects thymus - thymic hypoplasia
chr22q11 deletion
Cardiac issues
What are the physical signs of DiGeorge syndrome?
Dysmorphic face: cleft palate, low-set ears, fish-shaped mouth
What are the clinical symptoms of DiGeorge syndrome?
Hypocalcaemia, cardiac abnormalities
Variable immunodeficiency (absent/reduced thymus => affects T cell development)
What is Wiskott-Aldrich SYndrome (WAS)?
X-linked
Defect in WASP (protein involved in actin polymerisation => T-cells incorrectly model actin cytoskeleton = incorrect signalling)
What are the clinical signs of Wiskott-aldrich syndrome?
Thrombocytopaenia, eczema, recurrent infections
Describe the progression of Wiskott Aldrich syndrome?
Progressive immunodeficiency (T cell loss)
Progressive ↓ T cells; ↓ T cell proliferation
Ab production (↓ IgM + IgG; ↑ IgE + IgA)
Innate immunity defects involve which progenitor of haematopoiesis?
common myeloid progenitor (differentiates into macrophages + neutrophils)
What are the 2 types of innate immunity defects?
- Phagocyte defects
- Complement defects
What is the role of the ATM gene?
ATM gene stabilises DNA double strand break complexes during V(D)J recombination => defect in generation of lymphocyte antigen receptors & lymphocyte development
What are the types of phagocyte defects?
Quantitative (↓ number)
Qualitative
- Chronic granulomatous disease
- Chediak-Higashi syndrome
- Leukocyte adhesion defects (LADs)
What is chronic granulomatous disease?
Defective oxidative killing of phagocytosed microbes; mutation in phagocyte oxidase (NADPH) components
- Formation of granulomas (wall off microbes)
chronic granulomatous disease = phagocytosis defect. no destruction of pathogen by phagolysosome = pathogen resides in phagolysosome
patients form granulomas = immune attempt to surround the infection, areas full of macrophages unable to clear the pathogen = keep it there
How is chronic granulomatous disease diagnosed?
Diagnosis: Tests that measure oxidative burst:
- NBT test (nitroblue tetrazolium reduction)
- Flow cytometry assay dihydrorhodamine
Outline how an NBT reduction test is carried out?
- Control neutrophils + Patient neutrophils
- Incubate in nitroblue tetrazolium
- Activate using microbe / cytokines
- Checks production of active oxygen species
- If oxygen species produced; cells cleave active dye
= blue - Deficient patients have no colour as they are defective
How is a dihydrorhodamine assay used to diagnose chronic granulomatous disease?
Cells producing active oxygen species will cleave the dye making the cells fluoresce, if deficient no fluorescence will occur
Takes ~30 mins
What is Chediak-Higashi Syndrome?
- rare genetic disease
- defect in LYST gene (regulates lysosome traffic)
- neutrophils have defective phagocytosis - no phagosome-lysosome fusion = large granules
- repetitive, severe infections
What is the role of the LYST gene?
Regulates lysosome traffic
What causes recurrent infections in chediak-higashi syndrome?
Defect phagosome-lysosome fusion => defective killing of phagocytosed microbes => recurrent infections
How is Cjhediak-Higashi Syndrome diagnosed?
- Necreased number neutrophils
- Neutrophils have giant granules
What defects cause LAD (Leukocyte Adhesion Deficiency)?
- Defect in β2-chain integrins (LFA-1, Mac-1)
- Defect in sialyl-Lewis X (selectin ligand)
Describe the presentation of leukocyte adhesion deficiency
Skin infections, intestinal + perianal ulcers
How is leukocyte adhesion deficiency investigated?
↓ neutrophil chemotaxis
↓ integrins(adhesion molecules) on phagocytes (flow cytometry)
What is the effect of complement deficiencies?
Can affect different complement factors severe/fatal pyogenic infections (C3 deficiency)
Predisposition to infection with different pathogens
What are the symptoms of complement deficiencies?
Symptoms differ depending on C factor affected
What recurrent infections occur in complement deficiencies?
Recurrent infections (Neisseria) - deficiency terminal complex (MAC): C5, C6, C7, C8 & C9
Severe/fatal pyogenic infections (C3 deficiency)
SLE-like syndrome (C1q, C2, C4 deficiency)
What is Hereditary angioneurotic oedema?
Failure to inactivate complement (deficiency in C1 inhibitor); intermittent acute oedema skin/mucosa => vomiting, diarrhoea, airway obstruction
How are complement deficiencies investigated?
- measure individual components
- complement function: CH50 (haemolysis)
What are the aims of primary immunodeficiency treatments?
- Ig replacement therapy
- Bone marrow transplantation
- Gene therapy
- Prompt infection treatment
- Prevention of infection: isolation, antibiotic prophylaxis, vaccination
(not live vaccines!) - Good nutrition
What are the secondary immunodeficiency causes?
Infections: viral, bacterial Malignancy Extremes of age Nutrition (anorexia, iron deficiencies) Chronic renal disease Splenectomy Trauma/surgery, burns, smoking, alcohol Immunosuppressive drugs
Outline common secondary immunodeficiency infections
Viral:
- HIV, CMV, EBV,
- Measles
- Influenza
Chronic bacterial:
- TB
- Leprosy
Chronic parasitic:
- Malaria
- Leishmaniasis
Acute bacterial
- Septicaemia
What malignancies cause immunodeficiency?
- Myeloma
- Lymphoma (Hodgkin’s, non-Hodgkin’s)
- Leukaemia (acute or chronic)
What are the age extremities causing immunodeficiency?
prematurity
old age
How does prematurity cause immune vulnerability?
- infants < 6 months => maternal IgG
- premature delivery: interrupts placental transfer of IgG => infant Ig deficient
How does old age affect the immune system?
Decline in normal immune function
T-cell defects often impair …….
B-cell function/Ab production = Combined immunodeficiency
T-helper cells aid B-cells - TH2 cells, TFH cells
Selective IgA deficiency
IgA =
IgA = mucosal Ig - respiratory tract, urogenital tract, GI tract
-low serum + secretory IgA
PID Treatment - Stem Cell Gene Therapy
- Extract BM cells from patient
- Separate immune cell progenitors
- Insert normal gene via virus vector
- Reinsert stem cells into patient
HIV infection depletes ……
CD4+ T-cells
Blood cancer metastases deplete …..
leukocytes
HIV is a …..virus that infects ……… cells, causing their ………..
- retro
- CD4+ T
- depletion
When APCs(dendritic cells) bind to T-cell, transfers HIV particles to T-cells
Which infections are commonly associated w AIDS?
- Parasites - Toxoplasma
- Intracellular bacteria - Mycobacterium TB
- Fungi
- Viruses
What does HAART do?
Highly Active Anti-Retroviral Therapy
Stops HIV progressing to AIDS
