PMI02-3002 Flashcards
What are the four main components of the immune system?
T cells
B cells
Phagocytes
Complement
What is immunodeficiency?
Disease that is the result of loss of function/defective function/absence of a component of the immune system
What are primary and secondary immunodeficiencies?
Primary = genetically determined or result of developmental anomalies, rare
Secondary = acquired, caused by disease or immunosuppressive treatment, more common
What complement deficiencies can occur?
C1q/r/s, C2 or C4 deficiency (immune complex disease)
C3 deficiency
Factor B or D or properdin deficiency (similar to but not immune complex disease)
MAC deficiency
What is immune complex disease?
Inability to remove immune complexes with deficiencies in C1q/r/s or C2 or C4 (classical pathway)
Susceptibility to encapsulated organisms (S.pneumoniae, Neisseria)
What is the effect of a C3 deficiency?
Defective opsonisation so compromised removal via phagocytosis
Susceptibility to encapsulated organisms (Streptococcus, Neisseria)
What does Factor B or D or properdin deficiency result in?
Low C3b levels (no alternative pathway)
Pneumococcal and meningococcal infections
What is the effect of a MAC deficiency?
Unable to lyse bacterial cells
Recurrent infection with Neisseria meningitidis
Generally, what do complement deficiencies cause?
Increased susceptibility to bacterial infections
Especially Pneumococcus, Streptococcus, Neisseria
What deficiencies in phagocytosis can occur?
Problems in stem cell differentiation (neutropenia, leukocyte adhesion disease)
Lack of phagosome and lysosome fusion (Chediak-Higashi syndrome)
Defective intracellular killing (chronic granulomatous disease)
What is the difference between congenital and secondary (extrinsic) phagocytosis deficiencies?
Congenital = intrinsic deficiencies in differentiation, chemoattraction, intracellular killing
Secondary = result from deficiencies in another part of the immune system which affect phagocytosis
What conditions involving stem cell differentiation can cause phagocytosis deficiency?
Neutropenia
Leukocyte adhesion disease
What is leukocyte adhesion disease?
Lack of CD18 on neutrophils which binds to ICAM-1
Essential for recruitment/movement to site
What is Chediak-Higashi syndrome?
Lack of fusion of phagosome with lysosomes
Due to defective lysosomal trafficking regulator
What bacteria are those with Chediak-Higashi syndrome particularly susceptible to?
Staphylococcus aureus
Describe what causes defective intracellular killing in phagocytosis deficiency.
(Chronic granulomatous disease)
Defect in NADPH system (required for ROS formation)
So lack of oxygen-dependent killing
(Increased bacterial and fungal infection)
Generally, what do phagocytosis deficiencies cause?
Increased susceptibility to bacterial and fungal infections of skin and mucosal tissues
What is used to treat phagocytosis deficiency?
Antibiotics
Bone marrow transplant
What B cell/humoral deficiencies can occur?
Abnormal B cell development or lack of Th2 cell activity
B cells failing to develop (Bruton’s agammaglobulinaemia)
Common variable immunodeficiency (IgG and IgA)
No class-switching from IgM (hyper IgM syndrome)
What does abnormal B cell development of lack of Th2 cell activity cause?
Lack of antibodies
So less/no opsonisation
So defective phagocytosis
What is Bruton’s agammaglobulinaemia?
X-linked defect in Bruton’s Tyrosine Kinase (BTK)
BTK required for maturation of B cells from pre-B cells
Few/no mature B cells (so no antibodies)
Does Bruton’s agammaglobulinaemia occur more frequently in a certain population?
Male (infants) as it is X-linked
Protected for 6 months with maternal antibodies then recurrent bacterial infections
What is CVID?
Common variable immunodeficiency
Cause often unknown
IgG/IgA deficiency
Late onset (15-35yo)
Either no terminal differentiation of B cells of defective T cell signalling
What is hyper IgM syndrome?
Lots of IgM but little/no IgG in circulation as no class-switching has occurred
So lack of IgG opsonisation and phagocytosis
May be due to defective CD40 (B cell) or CD40L (T cell) affecting costimulatory signalling
Generally, what does humoral deficiency cause?
Recurrent extracellular bacterial infections (Pneumococcus, Streptococcus, Haemophilus)
Mainly encapsulated organisms
How is humoral deficiency treated?
Life-long periodic gammaglobulin injections
What cellular/T cell deficiencies can occur?
Lack of developed thymus (DiGeorge syndrome)
Stem cell defects or death of developing T cells (severe combined immunodeficiency syndrome)
MHC class II deficiency
What is DiGeorge syndrome?
Lack of developed thymus
So lack of T cells => susceptible to many infections and humoral deficiency
Hypoparathyroidism accompanies = hypocalcaemia
Congenital heart disease accompanies
What is SCID?
Severe combined immunodeficiency syndrome
Main cause is a defect in γ-chain co-receptor used in cytokine receptors for communication and development
Other causes could be deficiency in adenosine deaminase or purine nucleoside phosphorylase => metabolite build-up which inhibits DNA synthesis in T cells
What does MHC class II deficiency cause?
No mature CD4+ T cells due to defective APCs during thymus selection
Low aPC function, reduced T and B cell activation, no antibodies
Death by 5yo due to bacterial and viral infections
Generally, what do cellular deficiencies cause?
Opportunistic infections (also causes humoral deficiencies)
Often fatal in early life
How is cellular deficiency treated?
Bone marrow transplant
What are some clinical features of immunodeficiency?
Chronic or recurrent infections
Unusual microbial agents
Incomplete response to treatments
Diarrhoea
Recurrent abscesses
Recurrent osteomyelitis
Autoimmunity
Skin lesions (eg candidiasis, warts)
What can cause secondary immunodeficiencies?
Therapeutic drugs (chemotherapy, radiotherapy, immunosuppression)
Infection (eg HIV)
Metabolic disorders
Chronic infections (eg diabetes)
Malnutrition
Aging
Burns, trauma (loss of Ig through damaged skin)
What does HIV eventually cause?
AIDS (acquired immunodeficiency syndrome) => death
How many genes does HIV contain and what do they code for?
9 genes:
3 core genes for viral components
6 accessory genes that affect host
What are the surface proteins on HIV and how many are there?
gp120 + gp41 = gp160
~10-30 gp160 per virus
What are the general steps of HIV infection?
- Sequestration/capture by epithelial cells
- Langerhan’s cells capture HIV
- Transfer of HIV to Th cells/macrophages in submucosa or lymph node
- HIV replication
Describe the first step of HIV infection (sequestration).
gp120 binds and holds HIV at epithelial cells via heparan sulphate proteoglycans (eg syndecans) or galactosylceramide (Galcer)
Waits or gets internalised and integrated into genome (but epithelial cells do not produce new viruses)
What surface receptors on Langerhan’s cells help capture HIV?
DC-SIGN (binds lectin)
CD4
HSPGs (heparan sulphate proteoglycans)
Galcer (galactosylceramide)
What receptors are necessary for HIV to invade Th cells or macrophages?
CD4 = main receptor which needs a co-receptor:
- CXCR4 = Th cells (X4 viruses)
- CCR5 = macrophages (R5 viruses)
Describe how HIV enters Th cells and replicates.
- Virus binds CD4 and co-receptor (CXCR4)
- Viral envelope fuses with cell membrane and viral genome enters cell
- Reverse transcriptase copies viral RNA in DS cDNA
- Viral cDNA enters nucleus and integrates into host DNA
- T cell activation induces low level transcription of provirus (NF-κB)
- RNA transcripts are multiply spliced = translation of early genes (tat and rev)
- Gag, Pol, Env (late vial proteins) translated and assembled into virus particles which bud from cell
What is the function of the Tat gene?
Amplifies transcription (of HIV genes)
What is the function of the Rev gene?
Allows (HIV) RNA to be moved from nucleus to cytoplasm
Describe the course of an HIV infection.
Initial spike of HIV (viremia) causing flu-like disease = dip in CD4+ T cells (circulating is quickly replenished, mucosal less quickly) = 2-6 weeks
Asymptomatic phase = latency for 5-15 years
Symptomatic phase (viremia) = increase in population of HIV = decrease in CD4+ T cells => AIDS and lots of recurrent infections
What concentration of CD4+ T cells in AIDS?
< 200/μl
What are some signs and symptoms of acute HIV infection?
Headache, malaise, fever, nausea, weight loss, myalgia
Sores, thrush orally
Skin rashes
Vomiting
Liver and spleen enlargement
Lymphadenopathy
