Immunologic Disease (2/18, Nguyen) Flashcards
What are the two main starting cells for blood cell maturation?
Myeloid Stem Cells
Lymphoid Stem Cells
What are the 7 types of blood cells? (BENMPEL)
From Myeloid Stem Cells: Basophil Eosinophil Neutrophil Monocyte Platelets Erythrocytes
From lymphoid stem cells:
Lymphocytes
What are the main types of luekocytes? (NLMEB)
The white blood cells:
Never Let Monkeys Eat Bananas!
Neutrophils Lymphocytes Monocytes Eosinophils Basophils
What is the main role of neutrophils?
Acute inflammatory cells for phagocytosis.
What are the different types of lymphocytes?
CD4+ Helper T-Cells - influence all other cells of the immune system
CD8+ Cytotoxic T-Cells - directly kill virus-infected or tumor cells.
B-lymphocytes - secrete immunoglobulins (IgM, IgA, IgD, IgG, IgE)
Natural Killer Cells - lyse tumor cells and virally infected cells.
What is the main role of macrophages?
Ingest and kill microbes coated by antibody and/or complement.
What does MHC stand for, and what is it?
Major Histocompatibility Complex
The billboard!
What do MHC Class I molecules do?
On all nucleated cells
Present the peptides the cell is making
Present to CD8+ on cytotoxic T-cells
An altered MHC I = detected and killed
Normal MHC I = Prevent lysis of normal, healthy cell
What do MHC Class II molecules do?
Only on antigen presenting cells (APCs)
Present the antigens to CD4+ Helper T-cells
Why is MHC important to pathology?
Involved in:
transplant rejection
HLA and disease association
What is Ankylosing Spondylitis?
Chronic inflammatory disease of the axial skeleton
HLA Allele = B27
Which complement component is involved in the Classical Pathway?
C1q interacts with IgM and/or IgG to initiate the Classical Pathway.
What is the Alternative Pathway of complement?
Activated by bacterial cell walls
An endotoxin or venom binds to C3b
What are the 5 main roles of cytokines?
- Mediate innate immunity (from macrophages)
- Activate inflammatory cells (from T-cells)
- Recruit inflammatory cells (from macrophages and injured tissue)
- Regulate lymphocyte response (from many cells)
- Stimulate hematopoiesis
What do Macrophages 1 (M1) do?
Host Defense!
An over stimulation of M1 = cytotoxicity tissue injury.
What do Macrophages 2 (M2) do?
Anti-inflammatory and wound repair.
An over stimulation of M2 = fibrosis cancer
What does the global test of immune system involve?
- White blood cells count with differentials (% of each type)
- Complete Blood Count (CBC) with differentials
- Peripheral smear examination (# and shape of blood cells)
How is the function of a patient’s B-cells tested?
Test immunoglobulin levels and isotype titer
How is the function of a patient’s T-cells tested?
Use delayed type hypersensitivity testing
In Flow Cytometry and Fluorescence Activated Cell Sorting (FACS), what does the forward scatter provide information on?
The cell size.
In Flow Cytometry and Fluorescence Activated Cell Sorting (FACS), what does the side scatter provide information on?
The cellular internal complexity
What does “gating” refer to when using flow cytometry?
Selectively visualize the cells of interest while eliminating results form unwanted particles (like dead cells and debris).
What does a Flow Cytometry dot plot give information on?
A two-dimensional dot plots has regions on that can be sequentially separated, based on fluorescence intensity, by creating a series of subset extractions, termed “gates.”
What is first required for a hypersensitivity response (an excessive immune response)?
A prior exposure to the antigen (Ag) is required to “prime” the adaptive immune response.
What are the main causes for hypersensitivity reactions?
- Failure of self-tolerance to “self-antigens”
2. Uncontrolled or excessive response to foreign antigens
What is involved in a Type I hypersensitivity reaction?
Think: anaphylaxis, allergies, bronchial asthma
IgE
Mast Cells
Creates: vascular dilation edema smooth muscle contraction mucus production tissue injury inflammation
What is involved in a Type II hypersensitivity reaction?
Think: Autoimmune hemolytic anemia
IgG, IgM –>leads to phagocytosis or lysis of target cell by activated complement/Fc receptors
Creates:
inflammation
What is involved in a Type III hypersensitivity reaction?
Think: serum sickness, lupus
Deposition of antigen-antibody complex –> leads to complement activation –> recruits leukocytes
Creates:
inflammation
necrotizing vasculitis
What is involved in a Type IV hypersensitivity reaction?
Think: Contact dermatitis, multiple sclerosis, Type I diabetes, TB
Activated T lymphocytes (CD4 & CD8)
Creates: Perivascular cellular infiltrates Edema Granuloma formation Cell destruction
What are the 4 types of hypersensitivity reactions?
ACID Type I = Anaphylactic Type II = Cytotoxic Type III = Immune-complex Type IV = Cell-Mediated (delayed)
If you have an immunodeficiency disease, what are two mays that it may manifest?
- Recurrent pyogenic bacterial infections - due to a defect in immunoglobulin, complement, or phagocytic cells
- Viral, fungal, and intracellular bacterial infections - due to a defect in cell-mediated immunity
What are the main B-cell defect caused diseases discussed in this lecture? (BCSH)
B: Bruton (x-linked) agammaglobulinemia
C: Common variable immunodeficiency
S: Selective IgA deficiency
H: Hyper IgM syndrome
What are the main T-cell defect caused diseases discussed in this lecture? (TC)
T: Thymic hypoplasia –> DiGeorge Synd
C: Chronic Mucocutaneous candidiasis
What are the main combined B-cell and T-cell defect caused diseases discussed in this lecture? (X-WAS)
X: X-linked lymphoproliferative disorder
W: WAS
A: Ataxia telangiectasia
S: Severe combined immunodeficiency
What causes Bruton (x-linked) Agammaglobulinemia?
B-cell maturation stops after the initial heavy chain gene rearrangement.
Light chains aren’t produced and free heavy chains may be found in the cytoplasm.
What are the manifestations of Bruton (x-linked) Agammaglobulinemia, and when does it manifest?
Manifests at 6 months old - maternal immunoglobulin depleted.
Have recurrent infections by encapsulated bacteria (usually cleared by antibody opsonization).
With Bruton (x-linkeD) Agammaglobulinemia, how is the immune system affected in the peripheral blood, the lymph system, and GI tract?
Peripheral blood: Decreased # mature B-cells, low levels of all immunoglobulin.
Lymph node: Absent germinal centers, no plasma cells
GI Tract: No plasma cells
What causes Common Variable Immunodeficiency (CVID)?
Insufficient stimulus for B-cell activation…so, there are normal numbers of B-cells, but plasma cells are absent.
What are the manifestations of CVID, and when does it manifest?
There is an impaired antibody response to infection, so the patient has many pneumonia, sinusitis, and GI Infections.
Manifests at 15 - 35 years old.
What causes Selective IgA Deficiency?
B-cell defects or altered T-cell cytokine production that causes a deficiency of IgA.
Most common primary immunodeficiency!
What are the manifestations of Selective IgA Deficiency?
Recurrent sinopulmonary infections, diarrhea, bad breath, etc.
What causes Hyper-IgM Syndrome?
There is a failure to isotype switch due to defective CD154.
Usually, as B-cells mature, the initially express IgD/IgM and then progress to IgG, IgA, IgE. These don’t!!
What are the manifestations of Hyper-IgM Syndrome?
Normal to high levels of IgM and low serum levels of IgG, IgA, IgE
If there are low levels of IgG, may have recurrent pyogenic infections.
What is CD154 involved in?
The isotype switch from IgM to IgG, IgA, IgE
and
Macrophage activation
What causes Thymic Hypoplasia: Digeorge Syndrome?
22q11 deletion. May be associated with Accutane use during pregnancy.
This deletion causes malformation of the 3rd and 4th pharyngeal pouches:
thymus = NO T-CELLS
parathyroid,
portions of face & aortic arch
What are the manifestations of Thymic Hypoplasia? (CATCH-22)
CATCH-22
C: cardiac defect A: abnormal facies T: Thymic-hypoplasia C: cleft palate H: Hypo Ca2+ 22 = 22q11 deletion
What causes X-linked Lymphoproliferative Disease?
Gene defect Xq25 = deletion of SH2D1A gene.
SH2D1A codes for domain on the protein SAP, expressed in T and Natural Killer Cells.
SAP binds to a surface receptor inorder to modulate IFN-gamma cytokine.
Therefore, deletion of SH2D1A = no modulation of IFN-gamma = uncontrolled cell proliferation.
What are the manifestations of X-linked Lymphoproliferative Disease?
Bone marrow failure, irreversible hepatits, malignant lymphoma
What is WAS?
Wiskott-Aldrich Syndrome
What causes WAS?
Gene defect in the x-linked protein WASP.
WASP is responsible for intracellular signaling.
How does WAS manifest? (WIPE)
W: WAS
I: Immunodeficiency in T & B-cell response
P: purpura (red/purple skin discoloration)
E: eczema
What causes Ataxia-telangiectasia?
A gene defect in the ATM gene on chromosome 11q22.
ATM protein kinase are involved in DNA repair.
What is SCID?
Severe Combined Immunodeficiency
What is SCID caused by?
Severe defects in both humoral and cell-mediated immunity.
50% is due to x-linked mutation of the common gamma-chain gene on cytokine receptors.
50% caused by autosomal recessive mutation on ADA.
What are the manifestations of SCID?
Recurrent bacterial, viral , fungal, protozoan infections.
Deficiency of both T and B-cells.
What happens with ADA deficiency?
In SCID, ADA deficiency causes accumulation of adenosine and deoxyadenosine triphosphate metabolites. This inhibits DNA synthesis and is toxic to lymphocytes.
Basically, the lymphoid stem cell is not able to differentiate into either Pro-B cells nor Pro-T cells because of the ADA deficiency.
What is a disease caused by neutrophilic deficiency?
MPO Deficiency –> it is asymptomatic or a mild disease.
Example: Chronic granulomatous disease (CBD) = caused by deficiency of NADPH oxidase. These people have suppurative infections from bacteria and fungi that are catalase-positive.
What might cause a complement deficiency?
Any of the 31 proteins could be missing.
Can be passed along with any form of inheritance (autosomal dominant, dominant, x-linked, etc.)
What might cause unfettered C1 esterase activation?
Complement deficiency in C1 esterase inhibitor deficiency.
What three things might cause secondary immunodeficiencies?
Drugs
Malnutrition
Renal Disease
What secondary immunodeficiency can drugs (such as chemoradiation and immuosuppressants) cause?
Infections in HIV patients, cancer, and autoimmune diseases.
What secondary immunodeficiency can malnutrition cause?
Inadequate immunoglobulin synthesis
What secondary immunodeficiency can renal disease cause?
Loss of immunoglobulins.
