Immunodeficiency Flashcards
What is a primary (congenital) immunodeficiency?
β a defect in the immune system
What is a secondary (acquired) immunodeficiency?
β caused by another disease
What are three clinical features of immunodeficiency?
β Recurrent infections
β severe infections with unusual pathogens (aspergillus)
β unusual sites (liver abscess)
What are 6 signs of primary immunodeficiency?
β failure of an infant to gain weight or grow normally
β recurrent, deep skin or organ abscesses
β need for IV antibiotics to clear infections
β 2 or more deep seated infections
β family history of primary immunodeficiency
β persistent thrush after age 1
Where do you usually get infections in primary immunodeficiency?
β upper respiratory tract
What are 5 major B lymphocyte disorders?
β X linked agammaglobulinaemia β common variable immunodeficiency CVID β selective IgA deficiency β IgG2 subclass deficiency β Specific Ig deficiency with normal Igs
What is the frequency for the components of the immune system affected in primary immunodeficiency?
β antibody : 50%
β T cell : 30%
β Phagocytes : 18 %
β complement : 2%
Where is the defect in X linked agammaglobulinaemia?
β BTK gene (X chromosome)
What does the BTK gene encode?
β Brutonβs tyrosine kinase
Describe what would normally happen when a pre B cell expresses BTK?
β The BTK is downstream to the pre-B cell receptors
β if there is recognition of self-antigen the receptor has to send a signal via the Brutons tyrosine kinase
β the signal will rescue the cell from the default fate of apoptosis and it progresses to the next stage
What happens in patients with defective BTK?
β the cell dies by apoptosis because it cannot progress onto the next stage
What kind of infections do people with X linked agammaglobulinaemia get and where?
β recurrent bacterial infections
β lung, ears, GI
What are the results of investigations for someone who has X linked agammaglobulinaemia (immune cell levels)?
β B cells absent/low
β Plasma cells absent
β all Igs absent/very low
β T cells and T cell mediated responses are normal
What is the treatment for agammaglobulinaemia?
β IV Ig 200-600mg/kg/month at 2-3 week intervals
What should you not give to people who have X linked agammaglobulinaemia?
β Live vaccines
What are 3 examples of predominant T cell disorders?
β DiGeorge syndrome
β Wiskott-Aldrich syndrome
β Ataxia-telangiectasia
What cells does SCID involve?
β both T cells and B cells
What is the mode of inheritance of SCID?
β 50-60% X linked
β rest are autosomal recessive
What is the presentation of SCID?
β Well at birth but problems occur after the first month
β diarrhoea, weight loss, persistent candidiasis
β severe bacterial/viral infections
β failure to clear vaccines
β unusual infections (CMV, pneumocystis)
What can be the 3 causes of SCID?
β Common cytokine receptor Ξ³ chain defect
β RAG-1/RAG-2 defect
β Adenosine deaminase deficiency
What does having a gamma chain defect affect?
β signal transducing component of of receptors for IL-2, IL-4, IL-7, IL-9, IL-11, IL-15, IL-21
What is IL-7 needed for?
β survival of T cell precursors
What happens if IL-7 is absent?
β Defective T cell development
β Lack in B cell help
What happens with an adenosine deaminase deficiency?
β accumulation of deoxyadenosine and deoxy ATP
β toxic for rapidly dividing thymocytes
What are the results of investigations in people who have SCID (immune cell levels)?
β very low/absent T β normal/absent B β sometimes also absent NK (Ξ³ chain defect affecting IL-15 receptor) βIgs low β reduced proliferation and cytokines
What are the 6 treatments for people with SCID?
β isolation
β blood products from CMV negative donors
β IV Ig replacement
β treating infections
β bone marrow/haematopoietic stem cell transplant
β gene therapy for ADA and Ξ³-chain genes
What is the survival for someone with SCID with an early diagnosis, a good donor match and no infections pre-transplant?
β >80%
What is the survival for someone with SCID with a late diagnosis,chronic infection and poorly matched donors?
β <40%
What is DiGeorge syndrome also called?
βthymic hypoplasia
What is the cause of DiGeorge syndrome?
β Failure of development of the 3rd and 4th pharyngeal pouches
β one of the pouches is the thymus
What is the phenotype for DiGeorge syndrome?
β Cleft palate
β low set ears
β fish shaped mouth
What are the physiological abnormalities in DiGeorge syndrome?
β Hypocalcaemia
β Cardiac abnormalities
β Variable immunodeficiency (absent/reduced thymus which affects T cell development)
What is the mode of inheritance for Wiskott-Aldrich syndrome?
β X linked
What is the cause of Wiskott-Aldrich syndrome?
β defect in WASP ( protein involved in actin polymerisation)
β when T and B cells signal they need to remodel their cytoskeleton
What happens in Wiskott-Aldrich syndrome?
β progressive immunodeficiency ( T cell loss)
βprogressive decreased in T cells and T cell proliferation
β Ab production
What are the antibody levels like in Wiskott-Aldrich syndrome?
β decreased IgM, IgG
β increased IgE, IgA
What is the mode of inheritance of ataxia telangiectasia?
β Autosomal recessive
What is the cause of ataxia telangiectasia?
β Defect in cell cycle checkpoint gene (ATM)
What is the function of the ATM protein?
β sensor of DNA damage
β activates p53
β causes apoptosis of cells with damaged DNA
How does an ATM mutation affect the immune system?
β ATM stabilises DNA double strand break complexes during VDJ recombination
β If ATM is mutated then there is a defect in generation of lymphocyte antigen receptors and lymphocyte development
What are the symptoms of ataxia telangiectasia?
β Progressive cerebellar ataxia
β typical telangiectasis
β immunodeficiency
β increased incidence of tumors later in life
What are the two types of defects in innate immunity?
β complement defects
β phagocyte defects
What are 3 examples of phagocyte defects?
β Chronic granulomatous disease
β Chediak-Higashi syndrome
β Leukocyte adhesion defects (LADs)
What is the cause of chronic granulomatous disease?
β mutation in phagocyte oxidase (NADPH) components
How do reactive oxygen species form normally?
β In a phagocyte after the microbe is taken up there is the formation of active NADPH complexes by recruiting some subunits from the cytosol
β these convert oxygen into superoxide anions that are used to generate reactive oxygen species
How do granulomas form in granulomatous disease?
β There are defects in the components that lead to the formation of the superoxide anions
βcertain pathogens will not be able to be eliminated
β the formation of granulomas occurs (wall off the microbes) to try and contain the spreading of the infection to the rest of the body
What are the two tests for chronic granulomatous disease?
β NBT test
β Flow cytometry assay dihydrorhodamine
How does the NBT test work?
β Neutrophils are taken from patients and controls
β incubated with nitroblue tetrazolium
β activate them with a microbe or with cytokines to check if they can produce reactive oxygen species
β if they can produce them they will generate a blue color in the NBT
How does the flow cytometry assay for chronic granulomatous disease?
β activate the neutrophils
β if they can produce ROS they will cleave the dihydrorhodamine
What is the cause of Chediak Higashi syndrome?
β Defect in the LYST gene (regulates lysosomal traffic)
β neutrophils have defective phagocytosis
Why does having Chediak Higashi lead to recurrent infections?
β defect in phagosome-lysosome fusion β defective killing of phagocytosed microbes β recurrent infections
What three things about neutrophils point to a Chediak Higashi diagnosis?
β decreased numbers of neutrophils
β neutrophils have giant granules because the lysosomes canβt fuse properly
β they fuse with each other and not the phagosomes
What is the cause of LAD (leukocyte adhesion deficiency)?
β defect in Ξ²2 chain integrins (LFA-1, Mac-1)
βDefect in sialyl-Lewis X (selectin ligand)
How do you diagnose LAD?
β Delayed umbilical cord separation β diagnosis defect in Ξ²2 chain integrins (LFA-1, Mac-1)
What is the presentation of LAD?
β SKin infections
β intestinal and perianal ulcers
What are the lab investigation results for LAD (immune cell count)?
β Decreased neutrophil chemotaxis
β Decreased integrins on phagocytes (flow cytometry)
What are the 4 types of complement deficiency outcomes?
β Recurrent infections
β Severe/fatal pyogenic bacteria
β SLE like syndrome
β Hereditary angioneurotic oedema
What do complement deficiency symptoms depend on?
β C factor affected
What complement factor is deficient if you have recurrent neisseria infections?
β Deficiency terminal complex (MAC) : C5,C6,C7,C8, C8 & C9
What complement factor is deficient if you have recurrent pyogenic bacteria infections?
β C3 deficiency
What complement factor is deficient if you have SLE-like syndrome?
βC1q, C2,C4
What is hereditary angioneurotic oedema?
β failure to inactivate the complement
β deficiency in C1 inhibitor
What does hereditary angioneurotic oedema lead to?
β Intermittent acute oedema skin/mucosa leading to vomiting, diarrhoea, airway obstruction
What are the two investigations for complement deficiencies?
β Complement function : CH50
β measure individual components
What are the 6 treatments for primary immunodeficiency?
βImmunoglobulin replacement therapy βBone marrow transplantation βGene therapy βPrompt treatment of infection βPrevention of infection : isolation, βprophylaxis, vaccination βGood nutrition
What are the 8 causes for secondary immunodeficiency?
βInfections : viral,bacterial βMalignancy βExtremes of age βNutrition (anorexia, iron deficiency) βChronic renal disease βSplenectomy βtrauma/surgery, burns, smoking, alcohol βImmunosuppressive drugs
What are the 4 infections that cause secondary immunodeficiencies?
βViral : HIV,CMV,EBV,measles, influenza
βChronic bacterial : TB, leprosy
βChronic parasitic : malaria, leishmaniasis
βAcute bacterial : septicaemia
What are the 3 malignancies that cause secondary immunodeficiencies?
βMyeloma
βLymphoma (Hodgkinβs, non-Hodgkinβs)
βLeukaemia (acute or chronic)
What would cause an infant to be Ig deficient?
β Premature delivery
What two age groups have secondary immunodeficiency?
β Premature
β old age
