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126 Cards in this Set
- Front
- Back
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What is immunodeficiency?
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Result of a diverse group of abormalities of the immune system that mostly leads to an increased incidence of infection
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What are the 2 types of primary immunodeficiency?
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Congenital
Hereditary |
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What are secondary immunodeficiencies?
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Acquired Immune deficiencies
->can be transient or permanent, but are acquired |
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What causes primary immunodeficiency?
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Mutations that affect any number of genes that control the expression and activities of immune responses
->these disease allow us to find defective genes |
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What causes secondary immuodeficiences?
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Diseases:usually viral sources like HIV
Environmental factors: toxins, burns etc Medical interventions: hospitals use a variety of drugs that cause immunosuppresion |
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What is neede to make a diagnosis of someone who is immunodeficient?
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Need to have a history of repeated infections
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How many inherited disorders are there?
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over 200
->these are also ass't with other pertubations of the immune system, though not all have to do with infection ->some can be involved in autoimmunity/cancer |
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What is the most common primary immunodeficiency? What is its incidence rate?
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Selective IgA deficiency
Incidence rate of 1 in 500 |
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What is the least common primary immunodeficiency?
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Good's Sydrome
Incidence rate: 1 in 500,000 |
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What are some other primary immunodeficiencies?
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Common variable immunodeficiency: 1in 50,000
SCID: 1 in 100,000 X-linked agammaglobulinemia: 1 in 100,000 Chronic granulomatous disease: 1 in 200,000 |
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Can deficiencies vary depending on location andd population?
Example? |
Yes
Selective IgA deficiency Caucasians: 1 in 500 Chinese: 1 in 4000 Japanese: 1 in 18, 000 |
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Which parts of the immune system can be compromised in immunodeficiency?
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Bone marrow precursor stem cells
Blood cells (lymphocytes, neutropohils, monocytes) Souble molecules (Ab, cytokines, complement components) Can also have malfunction in signalling molecules and signal transduction and cell development Can also affect any organs of the immune system |
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What are some general considerations of primary immunodeficiencies?
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Most patients are male (83%)
Majority are children less then 15 (~60%) Deficiencies are genetically pre-determined and can be X-linked recessive, autosomal recessive or may be sporasdic incidences |
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What are the different defects that can lead to primary mmunodeficiency?
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Differentiation defects
Immunoregulatory defects Changes in specific protein synthesis/defective proteins Enzyme deficiencies |
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What does diagnosis depend on?
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Increased frequency, severity and duration of infection
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What are some other clinical features of diagnosis for primary immunodeficiencies?
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Unexpected complications/unusual manifestations of infection:
routine infection in a place where it shouldn't be -get a normal infection more often then you should Infection by organisms that have low pathogenicity: oppurtunistic pathogens (C. albicans, pneumocystis, mycobacteria) Non-infectious manifestations in GI, endocrinologic or hematologic organ systems |
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What is the first thing to be breached in the immune system?
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External barriers: skinor mucous mbs
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What are the clinical situations normally ass't with primary immunodeficiencies?
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Recurrent respiratory infection
Persistent sinus infection Paucity of lymphoid tissue Failure to thrive in infants Skin lesions (rash, pyoderma, eczema, telangiectasia) Oral and perineal candidasis Diarrhea and malabsorption |
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What are the 4 categories that these defects can be placed in?
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-Humoral immunity defects
-Cellular immunity defects -Phagocytic cell defects -Complement defects |
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Describe humoral immunity defects.
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Most common defect
transient lack lack of Ig production in fist 6-12 months of life (cuz losing mother's maternally transferred Ig) -Child's IgG should start within 2-3 weeks and reach the normal range by 6 months, and IgA and IgMlevels start to increase after 6 months |
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What happens in Selective IgA deficiency?
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85% of time: no symptoms
15%: have other ass't abnormalities like IgG subgp deficiency Some ppl can develop sinusitis or bronchitis from respiratory tract infections Can also get GIT and endocrine problems |
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Can IgA be replaced in the body? What happens if they are?
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Cannot be replaced (unlike IgG)
Replace IgA and get anaphylaxis with blood transfusions and die |
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What is the cause of selective IgA deficiency?
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Maturation defect in B cells
->they don't normally differentiate into plasma cells and make IgA |
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What are the 4 subgroups of IgG?
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IgG1/2/3/4
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Describe IgG subgp deficiency.
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recurrent pyogenic infections ass't with this deficiency in certain patients primariy with IgG2/4
These ppl don't tend to have any symptoms -don't yet know what the significance of IgG subgroup deficiency is |
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What is common variable immunodeficiency CVID)? (late onset hypogammaglobulinemia)
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Defined by hypogammaglobulinemia
Causes a sharp decrease in IgG and at least one of either IgM or IgA ->To make a diagnosis, person must have hypogamma IgG (low lvls of IgG) with or without low IgM and IgA |
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Describe common variable immunodeficiency.
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Most important adult primary immunodeficiency
Can occur at 8-10 yrs old, but most ppl get it btw 20-30 Symptoms: recurrent sinusitis, pulmonary infections (bronchitis) Equally affects males and females Ass;t with gastrointestinal, endocrine and hematological disorders Ppl tend to be very skinny when they have this disease Heterogenous syndrom that compromises many disorders excluded from other disorders 30% of infected ppl have large spleen |
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What does the immune system of ppl with hypogammaglobulinemia or CVID look like?
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Low but PRESENT IgG and IgM
Low or absent IgA Low or absent B cells Low memory B cells Possible T cell defects: no memory of past Ag responses, low CD40 expression (t cell defects can lead to oppurtunistic infections: 10%) Low CD4+ cell numbers (Low CD4/CD8 ratio) |
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What do naive B cells express?
Memory B cells:? |
Naive: IgD, but no CD27
Memory: CD27, but no IgD (but 15% of memory B cells can have IgD -> means they're switched) |
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What are the genetics of CVID?
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Sporadic disease for most patients
10-20% of patients have at least one family member with CVID or selective IgA deficiency (Mostly caused by autosomal dominant inheritance) ->genetic predispositiokn but not for everyone Genetic defects identified in TACI, ICOS,CD19 and BAFF-R (account for 5-10% of all cases) |
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What are the survival rates of CVID?
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1/3 of patients die after diagnosis
Survival rate of 20years after diagnosis Male: 64% survival, 92% survival in age, ender, matched population Female: 67% survival, 99% survival in age, gender, matched population |
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Why does is take so long for a diagnosis for CVID to be made?
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CVID often ass't with upper respiratory problems
Can take 14 years before doctor does the right test: serum Ig test |
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What is a good indicator of whether these ppl are going to die in the short term?
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Proportion of B cells circulating in the blood
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What is the most common cause of death ass't with CVID?
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Primary cause is NO infection, but lymphoma
Lymphoma: cancer of lymphooid tissue, generally followed by chronic pulmonary infections avg age of females at death: 45.5 average age of males at death: 40 |
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What happens in Bruton's X-linked Agammaglobulinemia (XLA)?
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Patients have NO IgG (in CVID, IgG is low)
.: these ppl can't make Ab vs Ag or vaccinations |
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Describe XLA.
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Detected after first 6 months of life (cuz till then have maternal IgG)
Causes life threatening pyogenic infections fungal infections are rare (like with Pneumocystis carinii) Viral infections are mild and can cause fatal CNS infections |
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What does the immune system of a person with XLA look like?
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They have NO:
-B-cells: do have pre-B cells in BM that are normal -Plasma cells Rest of the immune system is normal (normal thymus, but lymph nodes, adenoids and tonsils are not enlarged) |
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What is the treatment for ppl with XLA?
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Antibiotics
Gamma globulin (only IgG) |
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What is the gene defect in XLA due to?
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defect in the tyrosine kinase of the Tec family: BTK (encoded on the X chr)
->Failure to inactivate PLC-y -> ultimately leads to maturation arreset of cells at the pre-B cell stage |
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Do you see immature B cells in a male affected with XLA?
In a carrier female? |
Male: defect in X-chr, don't see immature B cells
Female: carrier ->if defective x-chr is inactivated:normal immature V cells are made -> if normal X-chr is inactivated: immaure B cells don't develop |
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What can happen to pplwith XLA?
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Can developenteroviral infections
Can cause neurological defects Can get hearing loss, lethargy, seizures, coma, weakness and possibly death |
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What is Hyper IgM syndrom?
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IgG, IgA and IgE are low
IgM is normal or makedly elevated |
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What happens in hyper IgM syndrom?
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Limited IgM response to T-cell epenent Ag
Patietns develop recurrent pyogenic infections and get oppurtunistic infections with Penumocystis carinii pneumonia (PNP) Can develop autoimmune disorders and cancer |
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What is the defect in hyper Ig due to?
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T cell defect
-> defect in CD40L found on activated CD4+ cells -> these are essential to isotype switching and formation of germinal centers |
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What does a mutation in CD40L cause?
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Prevents T cells from signalling B cells throug the CD40 path
->result: no T cell help .: b cells can't make IgG/A/E No CD40/CD40L cross linking which causes a failure in B cells to up-regulate CD80 and CD86 (costimulatory molec that interact with CD28 and CTLA-4) |
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How can hyper IgM syndrome be diagnosed?
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Lymph node biopsy: seeing if germinal centers are present or not
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What else does a defective CD40 path affect?
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T cells can't deliver a signal to infected macropohages by engaging CD40 on the surface of the macrophages
->loss pf T cell help DECREASES IFNy and IL-12 -possible defect in T cell activation can limit antigen-specific T cell expansion |
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What are some other syndromes ass't with hyper IgM?
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Mutations in CD40 gene lead to defects in CMI (via the transduction path)
**Hypodrotic ectodermal dysplasis (NEMO deficienc) |
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What is NEMO important for?
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Cell signalling for triggereing NF-kB
.: deficiency in NEMO shows identica clinical presentation as in Hyper IgM |
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Where do the mutations in NEMO occur?
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zinc finger domain
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Which pathways can tirgger NF-kB?
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Canonical path
Non-canonical path |
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Which pathways is there a defect in if there's a defect in NEMO?
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Canonical path
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What is AID (activation-induced cytidine deaminase) deficiency?
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Caused by mutations in the AID enzyme
Syndrome related to Hyper IgM synrome |
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What happens in AID deficiency?
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B cells can't undergo Ig isotype switching and patients have hypogammaglobulinemia
B cells have severely reduced somatic hypermutations ->this is a milder immunodeficiency and is only in terms of Ab responses |
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Where do the following diseases occur in B cell development?
XLA Hypere IgMCVID IgA deficiency |
XLA: occur early in B cell dev'p .: don't get immature B cells
Hyper IgM: occurs right before class switching (except for IgM) CVID: ovvurs before B cells vbecome mature B cells or plasmid cells IgA deficiency: occurs before B cells beome mature or plasma cells, but for IgA producing cells only |
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What is DiGeorge's syndrome?
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Due to developmental defect
-occurs early in embryogenesis in the 3rd and 4th pharyngeal pouches -Occurs as a clinical triad -causes tetany in the few first days of life |
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What is the clinical triad that evelops in DiGeorge's syndrome?
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Depressed T cell immunity because of absent thymus
Congenital heart disease Hypoalcemia due to lack pf parathyroids |
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How is DiGeorge's syndrom diagnosed?
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Through lateral chest X-ray
->shows absence of a thyic shadow (thymic aplasia) |
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What are the facial features of a child with DiGeorge's syndrome?
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Hooded eyelids
Narrow nasa; a;e Bulbous nasal tip Protuberant ears Small mouth ->they ultimately develop learning disabilities and neuro-psychiatric disorders ->babies can get severe diaper rash caused by Candida |
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What is the cause of DiGerorge's syndrome?
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Impaired production and fct of T cells
->defect in CHR segment 22q11 |
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What does the immune system of someone with DiGeorge's syndrom look like?
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-Have low CD8+ cell count
-CD4+ and B cell numbers are normal ->increased risk for viral infections and autommune disorders ->the condition improves with age |
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Deletion of which gene in the 22q11 chr is responsible for some of DiGeorge's syndrome's signs?
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The TBX1 gene (delete a single copy of this and can get some of the sighns for this disease)
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What causes SCID?
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Variety of defects that occur
-> results in combined defect ->mot just a humoral or cellular defect, but a pathology that affects both arms of immunity |
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What kind of infections are usually ass't with SCID?
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Viral,fungal or parasitic infections
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How can SCID be treated?
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Bone marrow transplant
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What are the different types of SCID?
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1) X-linked SCID
2) Adenosine deaminase deficiency 3) Omen syndrome 4) Bare lymphocyte syndrome 5) CD8 lymphopenia |
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What is the cause of X-linked SCID?
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T cells fail to develop
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What is the y(c) chain of T cells important for?
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Signal transduction that interacts with JAK3 kinases
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What happens if there is a defect in the y(c) chain of the IL-2 receptor?
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Causes X-linked SCID
->other cytokine receptors (for IL4,7,9,15 and 21) share a y(c) and are defective in this type of SCID |
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What are these IL important for?
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T/NK cell development .: they dont develop properly in this disease
->normally 75% of lymphocytes are suppose to be T cells, but in SCID,T cell count is low (also for NK cells) |
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What happens to B cells in X-SCID?
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B cell count is normal, but their fct isn't normal cuz they're not gettin T cell help
-> no Ab production cuz no T cell help and lack of IL-4 receptors (cuz no y(c) chain) -> .: get SCID |
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What kind of diseases are ass;t with SCID?
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Fungal infections
Vaginiis (for women) Diaper rash |
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What is Adenosine deaminase deficiency?
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Caused by enzyme defects in ADA (adenosine deaminase)
->another related enz defect is in PNP (purine nucleotide phosphorylase) causing PNP deficiency ->Thiis is a form of SCID |
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What happens in Ommen syndrome?
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Can't rearrange antigen receptor genes because there are mutations in RAG-1 and RAG-2 (.: lack of RAG activity)
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What are ppl with Ommen's syndrome susceptible to?
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Oppurtunistic infections
These ppl develop rashes. eosinophilia, diarrhea and enlarged lymph nodes |
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What does the immune system of a person with Ommen's syndrome look like?
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-Normal or increased T cell counts
-All the T cells are activated and clonally expanded with a restricted repertoire (they will only make one particular type of T cell) -NO B cells -.the T cells are responsible for graft-vs-host phenotype |
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What are the 2 kinds of Bare Lymphocyte Syndrome (BLS)?
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BLS II: lack of MHC II
BLS I: lack of MHC I |
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What happens in BLS II?
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MHC II molecules aren't expressed on lymphocytes and thymic epithelial cells
.: not appropriate Ag recognition |
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What does the immune system look like in BLS II?
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CD4+ cells are few and can't be [psitively selected for since the thymus doesn't have MHC II molecules
CD8+ cells are normal since MHC I expression is normal ->.: ppl get SCID (cuz no Th cells) |
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What are the 4 mutations in genes for ppl who can't express MHC II?
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Gp A: gene CIITA
Gp B: gene RFXANK Gp C: gene RFX5 Gp D: gene RFXAP ->** this syndrome is not caused by mutations in MHC II genes, but in genes envoding gene regulatory ptns required for the transcriptional activation of MHC II promoters |
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What happens in BLS I?
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MHC I molecules aren't expressed on lymphocytes
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What does the immune system look like in BLS I?
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CD8+ cells are present, ut don't express the a:B TCR
->individuals develop primary respiratory infections or skin infections from bacteria |
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Where have gene defects been found in ppl who have BLS I?
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TAP 1
TAP 2 ->these genes encode for transporter ptns |
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What is the defect in C8 lymphopenia?
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Mutation in chr 2q12
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What does the Chr 2q12 encode?
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ZAP-70
-Tyrosine kinase important for T cell signallin and has an essential role in positive/negative selection of maturing cells in the thymus |
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What does the immune system look like in CD8 lymphopenia?
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CD4+ cells are in normal numbers
CD8+ cells are entirely absent |
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What is ZAP-70's role analogous to?
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PLC-y
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What is Wiskott-Aldrich Syndrome (WAS)?
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X-linked deficiency
->caused by a defect in chr segement Xp11.22 |
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Where does the gene defect occur is WAS?
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in the WAS protein (WASP)
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What is WASP responsible for?
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Cell structure integrity
.:WASP defects means a problem in the assembly of actin filaments |
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Where is WASP expressed?
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All hematopoietic cell lineages regulating lymphocyte and platelet development and fct
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What do patients who have WAS develop?
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Eczema
Recurrentinfections Platelet defects Respiratory infections (usually pneumococcal infections Autoimmune diseases Vasculitis Predisposition to malignancies -> patients rarely live past 30 yrs |
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What diseases are often ass't with WAS?
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Lymphopenia, lymphocyte depletion in the thymus or defective delayed type heypersensitivity (DTH)
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Wat can DTH testing detect?
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Defective T cells
Tetanus: since most people are vaccinated against it, there should be a response to it candida: since most ppl have been in contact with it over time |
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Would WAS patients have positive or negative DTH results?
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Negative
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What lvlsof Ig do ppl with WAS have?
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Normal or low Ig lvls
->but can't generate Ab response to polysaccharide agents |
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What kind of responses do ppl with WAS have?
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No response tomitogens
Poor cytotoxic T cell responses Imparied T cell help for B cell responses to polysac |
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What do ppl with Ataxia telangiectasia have?
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Immunologic, neurologic, endocrinologic, hepatic and cutaneuous abnormalities
Reccurent bacterial infections Increased risk of cancer Selective IgA deficiency in 50-80% of patients Hypoplastic thymus that lack Hassall's corpuscles .: patients have decreased T cells (mostly CD4+ cells) |
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What is Ataxia Telangiectasia due to?
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Defect in chr segment 11q22.3
-> encodes PI3 kinase-like ptn called ATM -> ATM is involved in cellular responses to DNA damage/cell cycle control |
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Which cells are affected in Chronic granulomatous diseases?
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Phagocytes (not B or T cells)
->this disease takes place in the 1st year of life |
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Whre is the gene mutation in chronic granulomatous diseases?
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In 1 of 4 genes encoding the 4 subunits od nADPH oxidase of phgocytes
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What does this mutation in NADPH oxidase create?
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Inability to produce superoxide molecules
Failure to activate oxidative burst of macrophages |
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What happens to ppl with Chronic granulomatous diseases?
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Develop pneumonias, skin and liver abscesses and osteomyelitis
Develop large granulomas |
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How is chronic granulomatous disease treated?
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**IFN-y
-immuniation Antibiotics Surgical drainage |
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Which cells are affected in Leukocyte Adhesion Deficiency?
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Neutrophils
->they can't migrate towards an inflammatory stimuli or adhere to vasclar endothelium |
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What is leukocyte adhesion deficiency caused by?
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absent B unit of three ell surface glycoptns belonging to the CD11 family
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ow is leukocyte adhesion disease diagnosed?
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Recurrent soft tissue infections
Delayed umbilical cord separation Severe periodontal disease No pus forms despite having a high WBC count |
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What happens in complement component deficiency?
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Deficiency in complement and most complement components
->a bit more rare immunodeficiency |
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What can the complement component deficiency be in?
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C2: most commonly reported
C2 and C4: ass't with recurrent pyogenic infection and connective tissue disease C5/6/7/8: ass't with recurrent Neisseria species infection. Can be treated antibiotics C1 esterase inhibitor: ass't with hereditary angioedema |
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How is a primary immunodeficiency diagnosed?
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Look at medical history
Take a physical exam Do lab testing |
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What should be looked for when looking at the historical diagnostic features of a primary immunodeficiency?
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-How kids respond to viruses through immunization
-Severity of infection : number of type, localization, medication, hospitalization -See if there's family history: find if there's a cosanguinity or premature deaths |
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When are the onset of symptoms for primary immunodeficiencies?
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Birth-3 months:
-phagocytic cell defects -complement defects-DoGeorge's syndrom 3-6 months: -SCID due to no maternal IgG 6-18 months: -X-linked agammaglobulinemia 18 months to adulthood: -CVID Complement defects |
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What is looked for when doing a physical?
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Inspection of tonsils
Palpation or lymph nodes Organomegaly (enlargement of the spleen in particular) Growth measurements to verify if kids are growing normally Skin lesions |
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Which lab tests are performed?
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-Measure specific Abs circulating in blood
-Verify T cell immunity -Verify neutrophils -Verify complement |
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How is specific Ab circulation measured?
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Quantitative Ig to see which classes of Ig are present/absent
IgG subgp determination Isohemagglutinins |
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how can T cell immunity be verified?
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Lateral chest x-ray in infants
DTH skin tests in kinds less than 2 |
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How can the state of neutrophils be measure?
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wbc count to see if its different then normal
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How can complement status be verified?
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Total hmolytic complement test
Determine C3 and C4 concentrations |
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How can these test be more specific?
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Ab: use anti-dohpteria/pneumococcus or hemophillu Abs or anti-bacteriophage Abs
T-cell immunity: immunophenotypig (see the total number of T cells and helper T suppressor cells), antigen reactivity (if the T cells proliferate properly to Candida), mitogen reactivity to PHA, nucleic acid enzyme assays (to see if there are specific enz defects that cause ADA deficiency) Neutrophil fct: nitroblue tatrazolium dye test, chemiluminescence, chemotaxis, leukocyte phenotypes Complement fct: quantitative measurement of complement components in blood, fctnal assas for complement components |
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What kind of therapy can be used vs primary immunodeficiencies?
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Ig replacement therapy by administering IV IG or subcutaneous Ig (SCIG)
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How can primary immunodeficiencies be treated if they are cellular defects?
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Bone marrow ransplants: from identical or aploidentical donors
Administer IL2 since it is an important cytokine for T cell fct Gene therapy in ADA deficiency |
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How can primary immunodeficiencies be treated if they are phagocytic defects?
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Administer prophylactic antibiotics
Avoid giving viral vaccines Administer IFN-y for pplwith Chronic granulomatous disease Bone marrow transplants |
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Do all diseases result in problems of the hematopoietic lineage?
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NO
Can have problems with malignancy, like in cancer |
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What happens in epidermodysplasia verruciformis?
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Ppl inheritantly predisposed to get warts and can undergo malignant transformations to become cancer
-->Squamous carcinoma' These ppl don't have visible immune or hematopoietic phenotypic defects, but they lack cellular rsponses to HPV .: cancer, in an immunodeficiency context, is related to having a coinfection with HPV |
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Which cytokine is produce less in epidermodysplasia verruciformis?
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IL10
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How is the paradigm being shifted for immunodeficiencies?
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There is a single phenotype per patient
.: instead of these dieficiencies being rare in diseases in children, they are now v=coommon problems to all of us ->frequency of having an immune deficiency has gone from 1 in 500,000 to 1 in 1200 ex: if there's a problem in TLR3-IFNa/B in children who get HSV, hey end up getting encephalitis Conventional thought: these diseases were rare, familial and onset in children Novel: they're common, sporadic and onset in adults |
