Flashcards in Exam #3: Immunodeficiency II Deck (63):
What is Hyper IgM Syndrome?
This is a condition characterized by normal to elevated levels of IgM, BUT an absence of IgG, IgA & IgE isotypes
What causes Hyper IgM Sydrome?
- Failure of helper T cells to induce B-cell isotype switching from IgM to IgG, IgA, & IgE
- Failure to activate macrophages to remove intracellular microbes
What is the genetic basis of Hyper IgM Syndrome?
- X-Linked mutation for CD40L (on T-cells)
- Autosomal recessive mutation for CD40 or "activation induced demainase," an enzyme required for isotype class switching
What are the defects/ manifestations caused by Hyper IgM Syndrome?
- Lack of opsonization leads to recurrent infection
- IgM reactions against blood cells can cause hemolytic anemia
- Susceptibility to pneumocystis jiroveci
What is DiGeorge Sydrome?
Partial or complete disruption of the 3rd & 4th pharyngeal pouch development leading to aplasia or hypoplasia of the thymus/ parathyroid
What are the features of DiGeorge Syndrome?
- T-cell defect
- Cardiac abnormalities
- Cleft Palate
What is the genetic basis of Di George Syndrome?
What are the clinical manifestations of Di George Sydrome?
- Difficulty clearing VIRAL & FUNGAL infections
- Facial defects
- Cardiac defects
What are the facial defects seen in Di George Syndrome?
- Low set ears
- Midline clefts
- Small mandible
What are the cardiac defects seen in Di George Syndrome?
- Right subclavian artery derived from pulmonary artery
What is the difference between Di George Syndrome with hypoplasia vs. aplasia of the thymus?
Hypoplasia= immune defect resolves by age 5
Aplaisa= requires transplantation of fetal thymus
What is SCID?
Severe Combined Immunodeficiency, a constellation of different syndromes that all share common defects in humoral and cell-mediated immunity
What are the two genetic mutations that result in SCID?
- Autosomal Recessive
What is the mutation in the x-linked form of SCID? What are the consequences?
Mutation of common gamma chain subunit of cytokine receptors that impair the ability for lymphocytes to develop & function
What is the autosomal form of SCID?
This is the form of SCID that is caused by adenosine deaminase deficiency; this enzyme breaksdown metabolites that are toxic to lymphocytes
What are the clinical features of SCID?
- Early onset thrush, diaper rash, failure to thrive
- Recurrent infections of all types
What is the treatment for SCID?
- Bone marrow transplant
- Gene therapy for ADA
What is Wiskott-Aldrich Syndrome? What are the characteristics of Wiskott-Aldrich Syndrome?
This is an X-linked disorder in male infants characterized by:
What is the genetic basis for Wiskott-Aldrich Syndrome?
- X-linked disorder in male infants
- Defect disrupts the ability to maintain cytoskeletal linkage of membrane receptors--> progressive depletion of T & B cells
What are the lab markers for WAS?
- Low IgM
- Normal IgG
- Elevated IgA & IgE
- No response to polysaccharide antigens
- Poor response to protein antigens
- Depletion of T-cells in the blood & nodal tissue
What are the clinical manifestations of WAS?
- Hemorrhagic diathesis
- Recurrent respiratory infections
- Pyogenic bacteria, viruses, fungi
- Early death w/out bone marrow transplant
- Increased lymphoid malignancies in survivors past 10
What is the link between immunodeficiency & autoimmunity?
1) Defects in T-cells also include defects in T-regulatory cells
2) Persistent activation increases the likelihood of aberrant T-cell activation, altered immune response, & generation of auto-reactive cells
What are secondary immunodeficiencies?
Immune impairments in previously healthy people caused by a variety of diseases & physiologic states
What are the states that impair immunity?
1) Extremes of age
2) Metabolic state
4) Infiltrative & hematologic disorders
5) Trauma/ infection
What is vertical transmission of HIV?
*****I.e. from mother to infant
Describe the binding of the HIV virion.
1) HIV gp120 binds CD4+ molecule on target cell
2) Needs chemokine co-receptors:
- CCR5, macrophages
- CXCR4, T-cells
3) HIV gp41 inserts into the target cell membrane & fuses the viral envelope with the cell membrane for fusion
Outline the entry & transmission of HIV.
1) Reverse transcriptase transcribes viral RNA genome to a DNA copy (cDNA)
2) Integrase (viral) causes "integration" of cDNA into host DNA in dividing cells
3) cDNA integrated into host DNA gets transcribed & produces new viral particle
What happens to CD4 cells when they're infected by HIV i.e. why are T-cells killed?
1) Viral replication kills the CD4 cell
2) Activation of uninfected to undergo apoptosis
3) Expression of HIV particle on the surface causes CD8+ cells to kill them
What are the immune effects of HIV infection?
1) Lymphopenia i.e. selective T-cell lymphopenia with diminished T-cell function
2) Polyclonal B-cell activation & hypergammaglobulinemia
3) Altered macrophage function with decreased MHC II expression & Ag presentation
What are the five effects of T-cell lymphopenia on the immune system?
1) CD4= decreased response to soluble antigens
2) CD8= decreased specific cytotoxicity
3) NK= decreased killing of tumor cells
4) B-cell= Decreased Ig production in response to new antigens
5) Macrophage= diminished cytotoxic ability, less IL-1, & poor APC
What are the phases of HIV infection?
1) Early, acute phase
2) Middle, chronic phase
3) Final, crisis phase
What are the characteristics of the early acute phase of HIV?
- Viral replication
- Viral seeding of lymphoid tissue
*****All lead to: Fever, sore throat, myalgias i.e. flu-sx
What are the characteristics of the middle, chronic phase of HIV?
Continued viral replication in lymphoid tissue
*****Lymphadenopathy, weight loss, night sweats, fatigue, fever
What are the characteristics of the final, crisis phase of HIV?
- Marked viral replication
- Depletion of T-cells leading to profound immune suppression
*****Fever, fatigue, weight loss, opportunistic disease, & neoplasm
Outline the timeline of immune response to HIV.
- CTL response 2-3 weeks post infection
- Humoral response starts roughly 6 weeks post infection
BOTH responses reach their peak ~12 weeks after infecition
What are the AIDS defining neoplasms?
1) Kaposi sarcoma
2) B-cell lymphomas
3) Primary lymphoma of the brain
4) Invasive carcinoma of uterine cervix & anus
What is are the mechanisms of B-cell lymphomas in HIV?
There are two mechanisms:
1) HIV infection increases follicular T-cells initially, signaling germinal B-cells (immature) to proliferate & become hyperplastic--leads to lymphoma
2) T-cell depletion leads to the acquisition of other viral infections that drive lymphoma
How does pnemocystitis jirveci pneumonia appear on microscopy?
- Alveoli filled with foamy exudate
- Interstititium thickened by a chronic inflammatory infiltrate
How does pnemocystitis jirveci pneumonia appear on silver staining?
What does mycobacterium avium-intracellulare infect in AIDS patients?
Small intestinal villus that leads to problems with malabsorption
****Will also be present in the spleen
Where do Toxoplasma abscesses occur in AIDS patients?
Putamen & thalamus
What are the characteristics of HIV encephalitis?
Mutlinuclear giant cells
What is pulmonary cytomegaloviurs? How does this appear under microscopy?
Lung infection that leads to thickened interstitum
- Microscopy there is a hallmark "HUGE" nucleus
What is Progressive Multifocal Leukoencephalopathy (PML)?
Oligodendrocytes "drop-out" causing demyelination--drives AIDS dementia
What do the lesions associated with Kaposi Sarcoma look like?
Painful purple or brown cutaneous nodules
What are the different classes of drugs that are used to treat AIDS?
1) Reverse transcriptase inhibitors
2) Fusion & entry inhibitors
3) Integrase inhibitors
4) Protease inhibitor s
What are the characteristics of HIV encephalitis?
Mutlinuclear giant cells
What is Kaposi's Sarcoma?
Endothelial/ vascular tumor seen on the skin
What causes Kaposi Sarcoma?
What is Amyloidosis?
This term refers to a broad group of disorders characterized by the extracellular accumulation of amyloid, a mis-folded protein that cannot be degraded
What is amyloid?
Amyloid= a pathologic proteinaceous substance deposited int the extracellular space
- Forms continuous non-branching fibrils
- cross-B-pleated sheet conformation
What does amyloid stain with?
H & E:
Congo red= pink/ red color in tissue deposits
Congo red + birefringence=
- yellow green fluorescence
What are the three most common pathologic forms of amyloid protein?
1) AL, amyloid light chain
2) AA, amyloid associated
3) AB amyloid
What is AL derived from?
Ig light chains produced by plasma cells
What is AA derived from?
Acute phase protein synthesized by the liver, SAA
What is AB derived from?
B-amyloid precursor protein found in cerebral lesions of Alzheimer's Disease
What is Amyloidosis?
This term refers to a broad group of disorders characterized by mis-folded protein that cannot be degraded & accumulates
How is amyloidosis classified?
- Presence of absence of pre-exisiting disease
- Chemical type
What is AL associated with?
Multiple myeloma or some other disorder of B-cells
What is secondary amyloidosis?
Amyloidosis that occurs secondary to a chronic inflammatory state
What disease states is AA associated with?
- Subcutaneous drug abuse
- Renal cell CA
- Hodgkin's Lymphoma
What is ATTR? What ATTR associated with?
Autosomal dominant deposition of a mutant transthyretin that is associated with PERIPHERAL NEUROPATHY