immunodeficiency syndromes (immunopathology IV) - lecture notes - julia Flashcards
what are some examples of primary immunodeficiency syndromes? (8)
- x-linked agammaglobulinemia (bruton’s)
- common variable immunodeficiency
- isolated IgA deficiency
- hyper-IgM syndrome
- DiGeorge syndrome
- Severe Combined Immunodeficiency (SCIDS)
- WIskott-Aldrich syndrome
- complement deficiencies
what are some examples of a secondary immunodeficiency syndrome? (2)
- AIDS
- chemo
what is the difference between a primary and a secondary immunodeficiency syndrome?
- primary is congenital
- secondary is acquired
what are the categories of primary immunodeficiency syndromes (the different possible genetic causes)? (3)
- x-linked
- autosomal
- dominant
- recessive - molecular basis unknown
which primary immunodeficiency syndromes are x-linked? (4)
- x-linked agammaglobulinemia (bruton’s)
- hyper-IgM syndrome
- severe combined immunodeficiency (SCIDS)
- Wiskott-Aldrich syndrome
which primary immunodeficiency syndromes are autosomal? which are dominant and which are recessive? (3 total)
- dominant:
- C1 inhibitor deficiency (hereditary angioedema_
- recessive:
- DiGeorge Syndrome
- SCIDS
for which primary immunodeficiency syndromes is the molecular basis unknown?
- Isolated IgA deficiency
- common variable immunodeficiency
describe the pathways of the normal immune system (which components are humoral and which are cellular, etc.)
which autoimmune disorders are b-cell deficiencies?
- x-linked agammaglobulinemia (bruton’s)
- common variable immunodeficiency
- isolated IgA deficiency
- hyper-IgM syndrome
what causes x-linked agammaglobulinemia?
- failure of B-cell precursors to develop into mature B cells
- due to genetic mutation in bruton tyrosin kinase (Btk) gene on X chromosome
- results in no plasma cells, no antibodies
what is the function of the bruton tyrosine kinase (Btk) gene?
- codes for a tyrosine kinase that’s required for signal transduction that’s necessary for Ig light-chain rearrangement and B-cell maturation
in what population would you expect to see x-linked agammaglobulinemia? when? how is it treated?
- seen almost entirely in males
- manifests around 6 months of age because this is when the maternal antibodies are depleated
- treat by replacing Ig via IV
what clinical presentation would you see in a patient with x-linked agammaglobulinemia?
- recurrent bacterial infections of the respiratory tract
- acute pharyngitis
- sinusitis
- otitis
- bronchitis
- pneumonia
- due to bacteria normally opsonized by antibodies
- haemophilus influenzae
- streptococcus pneumoniae
- staphylococcus aureus
- may also have enteroviral encephalitis due to enteroviruses that come in through the GI tract and are normally neutrolized by antibodies
- echovirus
- poliovirus
- coxsackievirus
- severe intestinal giardiasis due to parasite normally resisted by IgA
- giardia lamblia
what would the immune cell composition be in a patient with x-linked agammaglobulinemia? (ie what cells will you see and which ones won’t you see)
- decreased to absent B-cells in circulation
- decreased serum immunoglobulin
- normal marrow b-cell precursors
- normal t-cell mediated reactions
need flow cytometry to tell whether cells are b cells or t cells
what are the characteristics of common variable immunodeficiency? what causes it?
- hypogammaglobulinemia
- normal number of B cells but unable to differentiate into plasma cells
how would you differentiate common variable immunodeficiency from bruton’s?
- presentation will be similar but genders will be equally affected
- onset will be later in childhood or adolescence
what is the significance of the word “variable” in common variable immunodeficiency?
- refers to the heterogenous manifestation of the disease
- can include:
- recurrent infections
- chronic lung disease
- autoimmune disorder
- GI disease
- hightened susceptibility to lymphoma
in what population (and in what frequency) does isolaged IgA deficiency occur? what is the consequence of the disease (both in terms of labs and infections)?
- occurs in 1/1600 individuals of european descent
- patients will have low levels of serum and secretory IgA because the problem is in the production of IgA
- patients have increased risk for respiratory and GI disorders
what causes hyper-IgM syndrome?
- due to defect in ability of helper T-cells to deliver activating signals to B cells
- will have lots of IgM antibodies but not the other antibody types
- most due to X-linked mutation in gene encoding CD40L that’s required for class switching
how would you treat humoral immunodeficiency syndromes?
- immunoglobulin replacement therapy via IV
- 100 to 400 mg/kg of body weight every 3-4 weeks
- adjust the dose to prevent serious infection adn to achieve a rate of infection that is comparable to the general population
what are some T-cell deficiencies?
- DiGeorge Syndrome (thymic hypoplasia)
- SCID
- WIskott-Aldrich syndrome (WAS)
what causes DiGeorge syndrome? what is the conseqence?
- deletion of 22q11
- results in failure of development of 3rd and 4th pharyngeal pouches
- results in loss of T-cell mediated immunity
- overall results in tetany (muscle contraction), congenital heart defects
what types of infections would you expect to see in association with T-cell defects?
- bacteria
- bacterial sepsis
- viruses
- CMV
- EBV
- severe varicella
- chronic respiratory and intestinal infection
- fungi and parasites
- candida
- pneumocystis jiroveci
all of these are diseases that require cell-cell mediated clearance
what causes severe combined immunodeficiency (SCID)? (what cells are absent - not what’s genetically responsible)
- patients will have lymphopenia
- severe or absent T cells
- frequently low/absent B cells
- hypogammaglobulinemia
- patients won’t be making any antibodies/gamma globulins
what is the consequence of SCID? how is it treated?
- results in high risk or viral, bacterial and fungal infections
- treat with bone marrow transplantation
- death will occur within a year if it’s not treated
what are the genetic causes of SCID?
- 45% have a cytokine receptor deficiency - this receptor is involved in signal transduction for variety of IL receptors - impacts T-cell development
- this is X-linked, recessive
- 15% have ADA deficiency
- this is autosomal recessive
- results in accumulation of toxic derivatives impacting immature lymphocytes - so the lymphocytes just don’t mature
- other causes
- autosomal recessive (19%)
- unknown (all male - 11%)
- JAK3 deficiency (7%)
- other
what genetiacally causes wiskott-aldrich syndrome (WAS)?
- x-linked recessive
- due to mutation in Xp11.23 WAS protein
- function of this protein is unclear
what antibody and immune cells proportions/populations would you expect to see in a patient with WAS?
- low IgM
- normal IgG
- elevated IgA and IgE
- will not make antibodies to polysaccharide antigens
- will get progressive T lymphocyte depletion
what clinical symtoms does WAS cause? (3)
- thrombocytopenia
- eczema
- immune deficiency
how is WAS treated?
- bone marrow transplant eventually
- this is curative
- for the first few weeks of life, give the baby platelet tranfusion to keep him from loots of bleeding until he can have the transplant
what are the types of complement deficiencies that can occur? (4) what is the concequence of each deficiency (ie what will patients with these deficiencies be more susceptible to?)
- C2 (1:10,000)
- no increased risk of infection
- but increased risk of SLE-like autoimmune disease
- C3 deficiency (very rare)
- increased risk of bacterial infection
- C5-9 deficiency (very rare)
- increased susceptibility to neisseria infection => menigitis
- can also have C1 inhibitor deficiency
what is the cause of C1 inhibitor deficiency (hereditary angioedema)? what are the pathological consequences?
- due to unregulated C1, hagemann factor (FXII), Kallikrein and Plasmin
- results in mast cell degranulation and vaoactive peptide release
- get episodic edema of skin and mucosal surfaces (larynx, GI tract) due to stressor trauma
how does bone marrow change as you age?
- lots of cells when you’re young
- gets replaced by fat as you age
what does the HIV genome consist of? (apparently we’re supposed to have this memorized)
- gag
- pol
- env
what is encoded by the gag gene in HIV?
- overall, a polyprotein processed by a viral protease
- this consists of:
- matrix (p17)
- capsid (p24)
- nucleocapsid (p7)
- p6
what is encoded by the pol gene in HIV?
- stands for polymerase
- encodes a variety of viral enzymes including:
- PR (p10)
- RT and RNAse H (p66/51)
- IN (p32)
- all processed by viral protease (PR)
what is encoded by the env gene in HIV?
- gp160 envelope protein
- cleaved in ER into gp120 (SU) and gp41 (TM)
- gp120 mediates CD4 and chemokine receptor binding
- gp41 mediates fusion
how is HIV diagnosed?
the p24 capsid antibody is used in diagnosis
what is the target and action of anti-HIV protease inhibitors?
- both gag and pol products must be cleaved by viral protease inhibitors
- drugs that target these can affect the virus without targeting human cells
- these aren’t curative, but can suppress the virus
where does the lipid outer layer of HIV viruses come from?
derived from the host cell
what tissues does HIV initially infect and how does it spread?
- enters via blood or mucosal tissues
- infects T cells, dendritic cells, and macrophages
- infection becomes established in lyphoid tissues when T cells move to lymph nodes
- get a period of viremia when you can measure the virus in the blood
how does HIV infect cells?
- gp120 binds to CD4 receptor and chemokine co-receptors (CCR5 or CXCR4) on T cells, monocytes, macrophages, or dendritic cells
- binding creates a conformational change in the viral gp41 protein
- this allows for fusion of the virus with host cell
- the viral core enters the cytoplasm of the host cell
what can allow individuals to be immune to HIV infection?
- CCR5 polymorphisms seem to confer immunity because the virus can’t spread into the cells (its gp120 protein doesn’t bind)
what are the mechanisms for immunodeficiency caused by HIV? (4)
- direct cytopathic effect of replicating virus
- colonization of lymphoid tissue leading to progressive destruction
- chronic activation of uninfected cells leading to activation induced cell death
- killing of infected cell by cytotoxic t lymphocytes
how does HIV evade the immune system? (3)
- mutations frequent due to error prone replication
- virus has glycan shield that prevents antibody binding
- point mutations, insertions, and deletions can alter the positioning of sugars => ever-changing disguise
how does the detectable level of HIV change over the course of infection?
- intially there’s viremia and it can be detected in the blood
- at detectable levels about 1 week post infection
- antibodies knock down this initial viremia
- this can last for a long time, until T cells can no longer keep up with the destruction
- you can then no longer contain the virus
- then you again get viremia and also get disease this time
how soon after infection is HIV detectable?
- viremia after 1 week
- seroconversion detectable 3-7 weeks post exposure
what are the different clinical categories of HIV infection? (3)
- A: asymptomatic, acute HIV, or PGL
- B: symptomatic conditions
- C: AIDS-indicator conditons
what are some examples of category B conditions in HIV infection? (7)
- oropharyngeal candidasis (thrush)
- vulvovaginal candidiasis (yeast infection)
- pelvic inflammatory disease (PID)
- hairy leuoklakia (oral - cancer syndrome that’s normally suppressed)
- idopathic thrombocytopenic purpura
- peripheral neuropathy
- herpes zoster (shingles)
what are some category C aids indicator conditions? (5)
- active CMV infection
- mycobacterium avium-intracellulare infection
- toxoplasmosis of brain (due to toxoplasma gondii)
- pneumocystis jiroveci (won’t get this infection until T lymph gets below 200)
- kaposi’s sarcoma lesions
