Primary Immunodeficiency Disorders Flashcards
What is the difference between an autoimmune disease and a hypersensitivity?
Autoimmune- an organisms “self” cells are attacked by the immune system.
Hypersensitivity- the immune system reacts in excess to a seemingly harmless substance like pollen
What is a situation where we intentionally disregulate the immune system?
Use immunosuppressives to avoid transplant rejection
What is the difference between a primary and secondary immunodeficiency?
Primary- a gene defect (inherited)
Secondary- arises from infection (HIV), autoimmunity against immune cells, malignancies, steroid/drugs
What can primary immunodeficiency lead to?
Cancer because the immune system will not be able to control infections or cancer cells
What are 4 examples of your immune system “doing too much”?
- Autoimmune- attacks its own cells
- Hypersensitivity- overreaction to antigens
- Transplant rejection by host attacking donor
- GVHD when the donor tissue attacks the recipient
What kind of gene defect causes most PID?
single gene defect
What is the accepted prevalence of PID?
1/10,000 so about 400 babies a year in the US
Over 50% of PID are due to a defect in what?
Ab
The clinical presentation of PID depends on _______________________.
The component of the immune system that is deficient
What are the research validated warning signs that someone has a PID?
- Recurrent infections
- Infection by strange organisms
- Need for IV antibiotics to clear infection
- Family history of PID
- Failure to thrive
Failure to thrive in an infant is usually a defect in what structure in the immune system?
Need for IV antibiotics is usually a defect in what ?
Failure to thrive- T cell defect
IV antibiotics- phagocytic defect
What percent of WBCs is lymphocytes?
What percent of the lymphocytes are Bcells?
40% of WBC are lymphocytes
20% of lymphocytes are B cells
What percent of serum proteins are Ig?
What Ig is also found in secretions?
30% of serum proteins
IgA
What are the 3 ways that Ab participate in host defense?
- Neutralization- prevent toxin from acting on a host because a toxin can bind a cell receptor but toxin-Ab complex cannot
- Opsonization- extracellular bacteria are coated with Ab so they can be recognized by FcR on macrophages and other phagocytic cells
- Complement activation- Ag:Ab complexes activate the classical pathway of complement activation
What Ab crosses the placenta?
After the baby is born, when does it drop to the lowest level?
IgG–> nadir at 3-4 months
When do Ab levels reach adult levels?
10 years of age
If a baby has a defect in Ab production, when will you see clinical manifestation?
starting at about 3 months because that is when the mothers IgG no longer offers protective function
What are the five major disorders linked to faulty Ab production/B cell defect?
- Transient hypogammaglobulinemia in infancy
- IgA deficiency
- Hyper IgM
- X-linked agammaglobulinemia (XLA)
- CVID (common variable immunodeficiency)
What is the clinical presentation of transient hypogammaglobulinemia?
Prolonged IgG nadir so at about 3 months, the child will have low IgG, but normal IgA, IgM and IgE.
They respond to vaccines
What is the clinical presentation of IgA deficiency? (age of onset, deficient Ig)
The patient will have a complete absence of IgA.
The age of onset is variable.
What is the most common B-cell defect?
IgA deficiency
What is the presentation of CVID?
low IgG, with low IgA and/or IgM IgE
Most commonly associated with GI/respiratory problems.
Inadequate response to vaccines
Why would someone develop Hyper IgM?
if the B-cell is unable to class switch from IgM to IgE IgA IgG in the germinal center
What is the other name for X-linked agammaglobulinemia? What are the characteristics of this disorder?
Bruton’s agammaglobulinemia–> the patient will have no Ab because there is a defect in BTK (bruton’s tyrosine kinase) so the B cell can’t develop
What are the six major ways a person with Ab deficiency usually present?
- recurrent infections/sepsis (esp with encaspulated bacteria)
- Bronchiectasis
- Gastroentiritis
- Enteroviral meningoencephalitis
- Arthritis
- Infections by: encapsulated bacteria, GNR, Ureaplasma, enterovirus, protozoa (Giardia)
If you were looking at a histological sample of a patient’s spleen, and you noticed that it lacked germinal centers, what disorder would you hypothesize they had?
Bruton’s agammaglobulinemia (XLA)
What molecular defect is linked with XLA?
Defect in BTK
What molecular defects are linked with CVID?
CD19, ICOS, TACI, BAFF
Which B-cell immunodeficiency diseases are responsive to IgG therapy?
- XLA
2. CVID
What is the major sign that a patient has CVID?
They are unable to make Ab to vaccines
In what B-cell immunodeficiency disorder is there a lack of B cells?
XLA
What fraction of circulating lymphocytes are T cells?
2/3
What signal complex allows B-cells to isotype class switch from IgM to the other Igs?
CD40/CD40L (T-cell dependent)
CD40- B cell
CD40L- T cell
What immunodeficiency disorder could be a B-cell defect OR a T-cell defect?
- Hyper IgM (because to class switch you need CD40/CD40L interaction between B and T cells)
- some strains of SCID
What are the 5 features of a T-cell deficiency?
- recurrent severe or unusual viral infections
- Infections after live vaccines
- Failure to thrive
- GVHD from mother’s T-cells or blood transfusions
- Infections with mycobacteria, fungi, viruses
How many different molecular defects can cause SCID?
over 14
What is the only treatment for SCID?
SCT
All forms of SCID have no ______, however some forms many or may not have _____ or _____ cells.
SCID is associated with no T-cells
Some forms also lack B and/or NK cells
Different forms of SCID occur based on what condition?
Where the defect lies in the lymphocyte development and the lymphocyte phenotype
_________________ is the most common form of SCID and is due to mutations in ____________________.
X-linked SCID is the most common form and it is due to mutations in the common gamma chain which is a receptor for IL2, IL4. IL7, IL9, IL15 and IL21.
What cytokines rely on the presence of the common gamma chain as their receptor?
2,4,7,9,15,21
Patients with X-linked SCID lack what cells?
They still have B-cells (although not very effective ones)
But no NK cells or T cells
Autosomal recessive SCID is caused by a mutation in what?
What is their lymphocyte profile like?
JAK3 mutation which causes the person to have no T or NK cells, but still make B cells
T-B-NK+ SCID is caused by a mutation in what?
RAG 1/2.
This mutation will not have the BCR or TCR rearrange their genes causing the phenotype to lack B and T cells
Patients with what SCID disorder can also have Omenn’s syndrome?
What cells are elevated in Omenn’s syndrome?
T-B-NK+ with mutations in RAG1/2.
Eosinophils are elevated in Omenn’s
T-B-NK- SCID is characterized by a deficit in what?
What accumulates?
Adenosine Demainase (ADA) which is an enzyme in the purine salvage pathway. This patient accumulates dATP
T-B+NK+ SCID patients have a deficit in what?
Genes responsible for normal T cell development like IL7R, CD3 (gamma, delta,epsilon or zeta), CD45
What are the five major presentations of SCID?
What deficit is associated with each?
- X-linked = T-B+NK- = common gamma chain
- AR= T-B+NK- = JAK3
- T-B-NK+ = RAG1/2
- T-B-NK- = ADA
- T-B+NK+ = T-receptor gene
What age will SCID present?
usually before one year of life (frequently after 3 months when the protection of maternal IgG wears off)
Why is the thymus absent on a CXR for SCID?
Because there are no thymocytes in the thymus, but it is still present so if you do a SCT the thymus will repopulate and it will show up on the scan?
Why was SCID screening added to the Texas screening panel?
Because babies with SCID look normal and don’t show the defect until 3 months or so, so if it caught early, they can have SCT before they show symptoms
What is the screening test for SCID?
What other disorder can be screened with the same test?
Looking for TRECs (T-cell receptor excision circles) that are a byproduct of development as TCR rearranges. It can also screen DiGeorge.
What is the mutation in DiGeorge syndrome?
a missing segment on chromosome 22 (22q11.2)
What triad of symptoms is seen in DiGeorge syndrome?
- low or absent T cells because thymic aplasia
- hypoparathyroidism causing low Ca
- Congenital heart disease
Where do all the symptoms of DiGeorge syndrome manifest?
Along the midline
In addition to physical and facial abnormalities, what other symptoms are associated with DiGeorge?
Cleft palate, delayed speech, schizophrenia, difficulty feeding, behavioral problems
What is the most common cause of hyper IgM?
mutations in CD40L on activated T-cells that cannot bind CD40 on B cells
When a mycobacteria infects the body, what cells become activated? By what receptor?
What cytokine is produced?
What cells do the cytokine activate?
The mycobacterium activates macrophages or DC by the TOL receptor.
The DC/macro produce IL-12.
IL-12 acts on CD4 T cells and NK to produce IFN-gamma
When IL-12 acts on CD4 and NK cells, what do they produce?
What are the 2 roles of their product?
They make IFN-gamma which:
- stimulates macro/DC activation to increase anti-microbial function
- Stimulate T and NK cells to release cytokines to kill targets
If someone has a mutation in their IFN-gamma/IL-12 axis, what microbes are they especially susceptible to?
Intracellular bacteria like: Mycobacteria Listeria Histoplasma Nocardia
What is the major component of the phagocytic system?
Neutrophils that are filled with granules that kill microbes
What are neutrophils a major source of?
inflammatory mediators
What molecules allow neutrophils to roll along vascular endothelial cells?
What molecules bind them tightly?
selectins allow rolling and integrin allows adhesion
What is the major chemokine that directs neutrophils toward the infection site?
IL-8
What are three forms of disease associated with quantitative levels of neutrophils?
What are quantitative defects called?
- Congenital
- Autoimmune
- Cyclic
Quantitative defects in neutrophils are called neutropenia
What are the two diseases associated with functional defects in neutrophils?
- Chronic granulomatous Disease
2. Leukocyte Adhesion Defect
If neutrophils are lacking, what will the patient present with?
- soft absesses
- gingivitis
- mucousal ulcerations
- poor wound healing
- Delayed separation of the umbilical cord
- Infection by catalase + organisms
What 6 organisms are catalase +?
staph aureus serratia burkholderia nocardia mycobacteria fungal (asperigillus)
What is the consequence of infections with bacteria that were ineffective at being killed by neutrophils?
hypergammaglobulinemia
What are the two forms of chronic granulamatous disease?
X-linked and AR
What is the fundamental defect in chronic granulamatous disease?
inability of phagocytes to generate superoxide anions (ROS).
Mostly due to a defect in the NADPH oxidase pathway
What do aerobic pathogens produce when they are ingested by phagocytes?
Catalase to break down the H2O2 made by microbes
Why do catalase + microbes persist in CGD?
Neutrophils in CGD arent able to produce ROS because of a defect in the NAPDH oxidase system. As a result, they rely on the H2O2 made by the bacteria
What 2 lab tests are used to test for CGD?
- Nitroblue tetrazolium test (NBT)–> ROS will reduce the tetrazolium from yellow to blue. If the neutrophil is CGD, it will not change color
- Dihydrorhodamine Test (DHR) by flow cytometry–> if the neutrophil can oxidize, it will produce green fluorescence. It can differentiate between X-linked and AR
Which test can differentiate between X-linked and AR CGD?
DHR flow cytometry:
X-linked has no increase in fluorescence
AR has a small increase in fluorescence
What will carriers of CGD show on DHR flow cytometry?
a mosaic pattern of fluorescence
What is the major defect with Leukocyte Adhesion Deficiency?
What do the patients have trouble doing?
The phagocyte cannot stop, anchor and move to the site of infection from the bloodstream.
The patients cannot form pus, but develop infected tissue masses
What genetic defect causes LAD?
AR disorder due to defects in selectins or integrins leading to impaired chemotaxis and phagocytosis
Which complement cascade defect is autosomal dominant?
Deficiency in C1-INH (C1 estarse inhibitor) that stops complement activation.
What complement cascade defect is x-linked recessive?
Properdin deficiency
What are the four major clinical presentations of patients with complement deficiency?
- Blood-borne or systemic pyogenic infection with Neisseria
- Sepsis, bacteremia and memingitis
- rheumatologic disorders (C2, C4–> lupus)
- Hemolytic uremic syndrome and glomeronephritis because of Factor H defect
What does deficiency in C1-INH cause?
Hereditary angioedema (HAE) because Factor XXII becomes activated and activates kallikrein which catalyzes the formation of bradykinin and plasmin to activate C1 which cleaves C2 and C4 which increase vascular permeability and cause edema
How do you differentiate between edema caused by C1-INH deficiency and IgE reaction?
IgE has histamine and is itchy
What is the receptor for LPS?
TLR4
What do TOL receptors on endosomal membranes sense?
viral nucleic acids
What cytokines and chemokines are released when TLRs are activated?
IL-1, IL-6, IL-8, and TNFa that inflame tissue, produce fever and recruit neutrophils/monocytes
What are the major TLR defects in humans?
MyD88, IRAK, NEMO, and TLR4 TLR3
What kind of mutation is associated with Wiskott-Aldrich syndrome?
What is the triad of symptoms?
X-linked recessive mutation in the WASP gene
- eczema
- microthrombocytopenia
- immunodeficiency
What cells are affected by Wiskott-Aldrich syndrome?
What is the treatment?
T-cells, B-cells, and platelets
Treatment by SCT
What are the mutations in Hyper IgE syndrome (Job syndrome)?
STAT-3 and Tyk2
What is the clinical presentation of Hyper IgE?
pulmonary and skin infections, eczema, eosinophilia, facial abnormalities (horse faces)
What is the gene defect in X-linked lymphoproliferative disorder?
defect in SLAM (signaling lymphocyte activation molecule) assicated protein (SAP)
What virus are people with X-linked lymphoproliferative disorder prone to?
What is the only form of treatment?
EBV infections where dysgammaglobulinemia develops and lymphomas form.
Treated with SCT
What five things are on the screening test for immunodeficiencies?
- Blood cell count
* neutrophils
* leukocytes
* lymphocytes
* platelets - serum IgG, IgA, IgM
- Antibody level to vaccines (dipther,tetanus, HIB, pneumococcus)
- Lymphocyte subpopulations
a. T cells- CD2, CD3, CD4, CD8
b. B cells - CD19, CD20, CD21
c. NK- CD16/56 - Total hemolytic complement
What disorders can be currently screened?
- Ab- disorder
- Cellular defects
- Wiskott-Aldrich syndrome
- Neutropenia
- Classic Complement Defects
What disorders cannot be screened with current testing?
- Phagocytic defects - CGD, IL-12/IFN-g
- Toll Receptors
- NEMO
- Hyper IgE
- ALPS
- Alternative complement
