Exam 2 (Chapters 5-6) Disease Notes Flashcards
1
Q
How many spontaneous abortions are caused by chromosomal abnormalities?
A
50%
2
Q
Sickle Cell Mutation
A
Point mutation from glutamic acid to valine
3
Q
Example of mutation within noncoding sequence:
A
Hereditary anemias
4
Q
Cystic Fibrosis Mutation Type
A
Three-base deletion (NOT A FRAMESHIFT MUTATION)
5
Q
Example of a frameshift mutation:
A
Tay Sachs (four base insertion)
6
Q
Diseases with Trinucleotide Repeats
A
CGG: Fragile X Syndrome/Tremor-Ataxia
GAA: Friedrich’s Ataxia
CAG: Huntington
7
Q
Example of Pleiotropism
A
Sickle Cell - aside from the abnormal hemoglobin, it also causes “logjam” –> splenic fibrosis, organ infarcts, bone changes
8
Q
Autosomal dominant disorders usually involve?
A
Structural proteins and receptors for metabolic pathways
9
Q
Is Huntington dominant or recessive?
A
Dominant
10
Q
Is Marfans dominant or recessive?
A
Dominant
11
Q
Is Cystic Fibrosis dominant or recessive?
A
Recessive
12
Q
Is Ehlers-Danlos Syndrome dominant or recessive?
A
Dominant (for most types)
Type VI and VIIc are autosomal recessive
13
Q
Is Familial Hypercholesteria dominant or recessive?
A
Dominant
14
Q
Is Alpha1-Antitrypsin dominant or recessive?
A
Recessive
15
Q
Are Lysosomal and Glycogen Storage Diseases dominant or recessive?
A
Recessive
16
Q
How are Agammaglobulinemia, Wiskott-Aldrich, and Fragile X syndrome inherited?
A
X-linked recessive
17
Q
What is usually involved in autosomal recessive?
A
Enzyme proteins
18
Q
Which diseases show a problem in receptor mediated endocytosis?
A
Familial Hypercholesterolemia
Cystic Fibrosis
19
Q
Key Features of Marfans
A
Skeletal abnormalities: very tall, dolichocephalic, double jointed, scoliosis
Ocular changes: bilateral subluxation and dilation of lens (called ectopia lentis)
Cardiovascular lesions: mitral valve prolapse
20
Q
Most common cause of death due to Marfans:
A
Aortic Dissection
21
Q
Gene involved in Marfans:
A
FBN1 and FBN2
22
Q
Treatment for Marfans:
A
Beta Blockers
23
Q
What deficiency do all EDS types have in common?
A
COLLAGEN
24
Q
Main feature of EDS with lysyl hydrolase deficiency?
A
Type VI - Kyphoscolios
Look for scoliosis and ocular fragility
25
Major symptoms/progressions of Familial Hypercholesterolemia?
Atherosclerosis and Xanthomas
26
Treatment for FH?
Statins to suppress intracellular cholesterol synthesis
27
Different between primary and secondary accumulations in lysosomal storage disease?
Primary: incomplete catabolism of metabolite causes accumulation within the lysosome
Secondary: impaired autophagy, damaged mitochondria accumulates and cell undergoes apoptosis
28
Deficiency and Accumulation of Tay Sachs
Deficiency: Hexosaminidase
Accumulation: GM2 gangliosides
29
Deficiency and Accumulation of Mucopolysaccharidoses
Deficiency: iduronidases
Accumulation: heparan sulfate, dermatan sulfate
30
Key features of Tay Sachs:
Cherry red macula
Motor incoordination
Death usually occurs 2-3 years
31
Deficiency in Niemann-Pick Types A and B
Sphingomyelinase
| Gene is preferentially expressed from the maternal chromosome due to epigenetic silencing of paternal
32
Genes involved in Niemann-Pick Type C
MOST COMMON
| NPC1 and NPC2
33
Most common lysosomal storage disease:
Gaucher Disease
34
Accumulations in Gaucher Disease
Glucocerebrosidase
35
Important features of Gaucher Type 1
```
Pathologic bone fractures
No neurologic symptoms
Gaucher cells in the bone marrow
Splenomegaly
Pancytopenia
```
36
Important features of MPS
Hepatosplenomegaly
Coarse facial features
Mental retardation
Lysosomes show zebra bodies
37
Hurler Syndrome (MPS I-H)
Autosomal recessive
Hepatosplenomegaly
Corneal clouding
Coarse facial features
38
Hunter Syndrome (MPS II)
X-linked
| NO corneal clouding
39
Hepatic form of glycogen storage diseases:
Type I Glycogenosis - von Gierke disease
Autosomal recessive
Storage of glycogen in the liver
Hypoglycemia
40
McArdle Disease
Type V Glycogenosis
Muscle cramps after exercise
Deficiency in muscle phosphorylase
41
Type VII Glycogen Storage Disease
Deficiency in muscle phosphofructokinase
42
Pompe Disease
See symptoms in heart (cardiomegaly), liver, and muscle
43
Most common chromosomal disorder:
Trisomy 21 (Down Syndrome)
44
Most common cause of Down Syndrome:
Meiotic nondisjunction
45
Most common death for those with Down Syndrome?
Congenital heart disease - defects of the endocardial cushion, atrial defects, valve malformations
46
What are people with Down Syndrome more likely to develop?
Acute Leukemias
| Most commonly: acute megakaryoblastic leukemia
47
Important Features of Edwards Syndrome:
Trisomy 18
Meiotic nondisjunction
Rocker bottom feet
Polydactyly
48
Important Features of Patau Syndrome:
Trisomy 13
Low set ears
Overlapping fingers
49
What two diseases make up the Chromosome 22q11.2 Deletion Syndrome?
DiGeorge Syndrome and Velocardiofacial Syndrome
50
Features caused by DiGeorge vs Velocardiofacial:
DG: immune defects and hypocalcemia due to parathyroids and thymus defects
VCF: heart, learning disability, facial features
51
What are people with the 22q11.2 deletion at risk for developing?
Psychotic illness - schizophrenia and bipolar disorder
52
Major genes in 22q11.2 deletion:
PAX9 and TBX1
These are expressed in the pharyngeal mesenchyme
53
On what day does the inactivation of X chromosomes via lionization happen?
Day 5.5 of embryonic life
54
Most common cause of hypogonadism in males vs females:
Klinefelters vs Turners Syndromes
55
Features of Klinefelters:
Abnormally long legs
Hypogonadism
Lack of secondary sex characteristics
56
Two mechanisms causing Klinefelters on the X chromosome:
1. Uneven dosage compensation due to extra X's
| 2. Gene for androgen receptor becomes insensitive to testosterone
57
Mechanisms for partial monosomy in Turners Syndrome:
1. isochromosome of the long arm
2. ring chromosome
3. deletions of either the long or short arm
58
Most severely affected infants will appear at birth with:
Swelling of the dorsum of the hands and feet
| Swelling of the nape of the neck (cystic hygroma)
59
Other main features of Turners:
```
Short stature
Amenorrhea
Streak ovaries
Neck webbing
Looseness of skin on back of the neck
Congenital heart disease
```
60
Important gene in Turners:
SHOX
61
When do trinucleotide expansions happen in Fragile X vs Huntington?
FX: during oogenesis
HTN: during spermatogenesis
62
Morphologic hallmark of trinucleotide repeat diseases:
Accumulation of proteins in large intranucelar inclusions
63
Fragile X Syndrome is caused by a trinucleotide mutation in which gene?
FMR-1 (familial mental retardation 1)
64
Major features of Fragile X:
Macro-orchidism
Large everted ears
Mental retardation
65
Why do grandsons of normal transmitting males have a higher risk?
Amplification of the repeats happen during oogenesis, so the mothers will amplify the disease before passing it down
66
Why is Fragile X a loss-of-function disorder?
CGG repeats --> transcriptional silencing of FMR-1 --> lack of FMRP proteins
67
Mechanism behind Fragile X Tremor/Ataxia?
Toxic gain of function mechanism
68
Why is the Tremor/Ataxia verion considered toxic?
FMR1 gene is continuously transcribe and there is excess FMRP proteins and mRNA
69
Leber hereditary optic neuropathy is what type of disease? Main features?
Mitochondrial disease - neurodegenerative
| Manifests as bilateral loss of central vision
70
Two diseases caused by genomic imprinting?
Prader-Willi and Angelman's
71
Features of Prader-Willi
```
Mental retardation
Short stature
Hypotonia
Hyperphagia - can't stop eating, high BMI
Hypogonadism
```
72
Why are those diagnosed with Angelmann's referred to as "happy puppets"?
Mentally retarded, with inappropriate laughter
73
Prader-Willi vs Angelmann Imprinting:
PW: maternal chromosome imprinted, rely on paternal but that gets deleted
A: paternal chromosome imprinted, rely on maternal, but that gets deleted
74
Genes in Prader-Willi vs Angelman:
PW: SNORP
A: UBE3A
75
What does FISH stand for?
Fluorescence in Situ Hybridization
76
Importance of NOD-like Receptors (NLRs)
Cytosolic reeptors
Recognize products of necrotic cells, ion disturbances, microbial products
Signal via the inflammasome complex
77
Inflammasome Complex
Activates caspase-1 --> IL-1 --> recruits leukocyte and induces fever
78
Mutations in TLRs vs NLRs
TLR: immunodeficiency syndromes
NLR: autoinflammatory syndromes
79
C-type Lectin Receptors: (CLRs)
Found on macrophages and DCs
| Detects fungal glycans
80
RIG-like Receptors (RLRs)
Found in the cytosol of most cell types
| Detects viral nucleic acids
81
GPCRs:
On neutrophils, macrophages, and leukocytes
| Recognize N-formylmethionyl residues on bacteria
82
Mannose Receptors
Recognize microbial sugars
83
Best antiviral defense secretion:
Type 1 interferon
84
Enzyme in developing lymphocytes that mediates recombination:
RAG-1 and RAG-2
Defects here = no mature lymphocytes
85
What do NK-T cells do?
Recognize glycolipids displayed by CD1
86
Proteins found on the B cell receptors:
Iga and Igb, Type 2 complement receptor (CD21), and CD 40
87
Which cells are most important as APCs for activating T cells?
Dendritic Cells
88
Immature DCs within the epidermis are called:
Langerhan Cells
89
Follicular DCs are found where? and do what?
Found in germinal centers of lymph nodes
Select B cell with highest affinity for antigens
Can also trap antigens with C3b
90
What are the main targets of NK cells?
Viruses and tumor cells (irreversibly stressed and abnormal cells)
91
What markers are used to identify NK cells?
CD16 (responsible for ADCC) and CD56
92
How are NK cells regulated?
They have inhibitory and activating receptors
IL-2 and IL-15 stimulate proliferation
IL-12 activates killing and secretion of IFNy
93
Genes for HLAs are found where?
On chromosome 6
94
Class I MHC Molecules use which HLAs?
HLA-A, HLA-B, and HLA-C
95
Class II MHC Molecules use which HLAs?
Encoded for in the HLA-D region:
| HLA-DR, HLA-DQ, and HLA-DP
96
What are colony stimulating factors?
Cytokines that stimulate hematopoiesis
Examples: GM-CSF and IL-7
97
Condition where you'd rather inhibit cytokines?
RA = with TNF antagonists
98
Condition where you'd rather administer cytokines?
Boosting hematopoiesis and defense against viruses
99
What type of antigen stimulates a T-independent response from B cells?
Polysaccharides and Lipids - stimulate IgM
100
Which cytokines induce isotype switching?
IFNy and IL-4
101
What is caused by Type I hypersensitivities?
Allergies, anaphylaxis, and atopy
Caused by production of IgE by Th2 cells/B cells
102
Main type of cell in Type II hypersensitivity?
B cells - make IgG and IgM antibodies to activate complement/phagocytosis
103
Main type of cell in Type III?
Immune Complexes - antigens and antibodies that cause inflammation and fibrinoid necrosis
104
Main type of cell in Type IV?
T cells - Th1, Th17, and CTLs (CD4 and CD8)
| Delayed type of hypersensitivity
105
Order of cell appearances in Type I?
Immediate reaction: predominantly mast cells
| Late-phase reaction: mostly eosinophils, activated T cells
106
What are the preformed mediators secreted by mast cells?
Vasoactive amines (Histamine), Enzymes (proteases), and Proteoglycans (heparan and chondroitin sulfate)
107
Which secondary mediators are made de novo in mast cells?
Leukotrienes, Prostaglandin D2 (causes bronchospasm), and Platelet-Activating Factor (recruits platelets)
108
Treatment for immediate vs late-phase Type I reaction:
Immediate: anti-histamine
| Late-phase: anti-inflammatory (steroids)
109
Which type of hypersensitivity has autoantibodies?
Type II
110
Mechanism behind Type II:
Opsonization and Phagocytosis
111
Examples of conditions where we see Type II?
Blood transfusions
Erythroblastis Fetalis
Autoimmune hemolytic anemia
Drug reactions
112
What type of hypersensitivty are Myasthenia Gravis and Graves' disease?
Type II
113
What is Goodpasture Syndrome? Type of hypersensitivity?
Pulmonary-renal disease - attacks self tissues causing nephritis and lung hemorrhage
Type II Hypersensitivity
114
Main clinical manifestations of Type III?
Affects the kidneys (glomerulonephritis), joints (arthritis) and vessels (vasculitis)
115
Prototypic examples of Type III?
Acute Serum Sickness
116
Why is organ damage a Type III response?
The high pressure of blood flow pushes immune complexes to be concentrated and deposited
117
How can you measure the progress of the active phase of Type III?
C3 levels - it will decrease as it is being consumed
118
Common disorders caused by Type III?
SLE, glomerulonephritis, reactive arthritis, serum sickness
119
What is the prototypic example of Type IV?
Delayed Type Hypersensitivity (DTH)
120
If the macrophages continue to be activated, what happens?
First form epithelioid cells --> granulomas
To prevent this, give an IFNy antagonist
121
Disorders caused by Type IV?
RA, MS, T1D, IBD, psoriasis, and contact sensitivity
122
Central tolerance for T cells:
As they mature in the THYMUS, those that recognize self antigens are either killed by apoptosis or made into regulatory T cells
123
Central tolerance for B cells:
As they mature in the BONE MARROW, those that recognize self antigens either undergo receptor editing or are killed by apoptosis
124
Mechanisms of peripheral tolerance:
Anergy
Suppression by regulatory T cells
Deletion by apoptosis
125
Immune-Privileged Sites:
Eyes, testis, and brain
126
What diseases is PTPN22 associated with?
RA, T1D, and IBD
Due to a functionally defective phosphatase
127
What disease is NOD2 associated with?
Crohn's
Receptor is ineffective at sensing gut microbes
128
What diseases is CTLA4 associated with?
T1D and RA
T cell responses are inhibited by regulatory T cells
129
What disease is ATG16 associated wit?
IBD - involved in autophagy
130
Examples of molecular mimicry:
Rheumatic heart disease --> antibodies against strep also share sequences with myocardial proteins
EBV and HIV --> causes polyclonal B cell activation which may create autoantibodies
131
Mechanisms of injury behind SLE:
Formation of multiple autoantibodies leads to immune complexes being deposited all over
Self-tolerance fails
132
Most popular SLE symptoms:
Malar rash, photosensitivity, arthritis (nonerosive), renal disorders (proteinuria), specific antibodies found in serum, inflammation of serosal membranes, Liebman-Sacks verrucous endocarditis
133
SLE predominantly affects:
Women mostly
| Blacks and Hispanics at higher risk
134
Most widely used testing for detecting ANAs is:
Indirect Immunofluorescence
135
Which antibodies are diagnostic for SLE?
Anti-Smith antigen and Anti-DNA for double stranded
136
Why might SLE patients test falsely positive for syphilis?
Because 30-40% of SLE patients also have antiphospholipid antibodies
137
Though many factors may cause SLE, what specific locus has been linked?
HLA-DQ
138
Environmental factors that may cause SLE:
Exposure to UV light: exacerbates the disease, may induce apoptosis and production of IL-1
Gender bias: SLE partly attributed to sex hormones
Drugs: hydralazine, procainamide, isoniazid
Microbiome
139
Treatment for SLE:
Corticosteroids or immunosuppressive drugs
140
Most common cause of death due to SLE:
Renal failure and recurrent infections
141
Chronic Discoid Lupus
Mostly involves skin - characterized by skin plaques on face and scalp
See depositions of C3 and Ig
142
Subacue Cutaneous Lupus
Also involves skin mostly - widespread rash that is superficial and nonscarring
Ab for SS-A
143
Drug-Induced Lupus
May develop after administering certain drugs (like isoniazid or anti-TNF therapy for RA)
Renal and CNS are NOT affected
Ab for histones is high
144
6 Types of Kidney Lesions in SLE:
1: least common - only seen in electron microscopy
2: no involvement of glomeruli
3: less than 50% glomeruli affected
4: most common and most severe
5: diffuse
6: represents end stage renal disease
145
Main features of Sjogren Syndrome?
Dry eyes (blurry vision), dry mouth (dysphagia), destruction of lacrimal and salivary glands, parotid gland enlargement
146
Primary form of Sjogren is called?
Sicca Syndrome
147
Important antibodies in Sjogren?
Anti-SS-A (Ro) and Anti-SS-B (La)
148
Who is most susceptible to Sjogren?
Women, ages 50-60
149
How is Sjogren diagnosed?
With a biopsy of the lip
150
Lymph nodes are hyperplastic in Sjogrens. What type of cells are seen?
Initially: polyclonal T and B cells
Later: B cells take over, putting them at risk for marginal zone lymphoma (5%)
151
Two types of scleroderma and the differences:
Diffuse: widespread skin involvement, rapid progression and early visceral involvement
Limited: skin involvement on forearms, fingers, and face
- late visceral involvement
- may develop CREST syndrome
152
What is involved in CREST syndrome?
```
C: calcinosis
R: Raynaud's phenomenon
E: esophageal dysmotility
S: sclerodactyly
T: telangiesctasia (spider veins)
```
153
Pathogenesis of Scleroderma
Autoimmunity: CD4+ T cells, Th2
Vascular damage
Fibrosis (myocardial and interstitial lung fibrosis)
154
In patients with systemic sclerosis, death is usually caused by what?
Renal failure, cardiac failure, or malabsorption syndrome
155
Who is more susceptible to developing scleroderma?
Female to male ratio is 3:1
| Most aged 50-60 years old
156
Clinical features and progressions of systemic sclerosis:
Raynaud phenomenon
Dysphagia (90%)
Mild proteinuria (30%)
Malignant hypertension --> may progress renal failure
157
What causes malabsorption syndrome in systemic sclerosis?
Loss of villi in the intestines
158
Mixed Connective Tissue Disease
Mixture of features from SLE, systemic sclerosis, and polymyositis
Characterized by antibodies to U1RNP
Symptoms: pulmonary hypertension, interstitial lung disease, and renal disease
159
IgG4-Related Diseases
Tissue infiltrates dominated by IgG4 plasma cells
Storiform fibrosis: looks like a wheel
Increased serum IgG4
*mostly affects middle-aged men and older men*
160
Difference between direct and indirect pathways of rejecting a graft?
Direct: uses both Class I and II MHC molecules
Indirect: only uses Class II MHC molecules and causes a delayed type hypersensitivity (type IV)
161
When is hyperacute rejection likely?
When the patient already has preformed antibodies (presensitized):
- previously rejected transplant
- multiparous women
- previous blood transfusion
162
When does acute antibody-mediated rejection occur?
Antidonor antibodies are produced after transplantation
| Initial target: graft vasculature
163
How does chronic antibody-mediated rejection happen?
Develops insidiously
| Primarily affects the vascular components
164
Drugs used for immunosuppressive therapy:
Steroids, mycophenolate mofetil (inhibits lymphocyte proliferation), tacrolimus (inhibits T cells), IVIG
165
Major risk of immunosuppression:
Susceptibility to opportunistic infection by the polyoma virus --> kidney specific, causes graft failure
166
Rejection patients also at risk for developing:
- EBV-induced lymphoma
- HPV-induced squamous cell carcinoma
- Kaposi sarcoma
167
For polyoma or other viruses after rejection, treatment includes:
Decreasing the levels of the immunosuppressive drug to allow the immune system to fight off the virus
168
Graft v Host Disease is most commonly seen after what?
HSC transplantation
169
Acute GVHD presents as:
Occurs within days to weeks
| Presents with skin (rash), liver (jaundice), and intestines (bloody diarrhea)
170
Chronic GVHD presents as:
Occurs within months to years
| Presents with skin (fibrosis of dermis), liver (chronic liver disease), GI (esophageal strictures), involution of thymus
171
When are primary immunodeficiencies seen?
In infancy, from about 6 months to 2 years
| Telltale sign of this: recurrent infection
172
Leukocyte adhesion deficiency 1:
Mutations in CD11/CD18 integrins
| See recurrent infections due to inadequate granulocyte
173
Leukocyte adhesion deficiency 2:
Absence of Sialyl Lewis C - E and P selectins cannot bind
| See recurrent infections
174
Chediak-Higashi Syndrome
Inherited defect in phagolysosome function - unable to kill microbes
175
Chronic granulomatous disease
Activated macrophages --> granulomas
X-linked (most common) and autosomal recessive both have a defect in phagocyte oxidase
176
Myeloperoxidase Deficiency
Defective MPO-H2O2 system
177
Defect in TLR 3
Receptor for viral RNA
178
Affected infants with SCID present as:
Prominent thrush, extensive diaper rash, failure to thrive
| May also present with a morbiliform rash (looks like measles, sign of GVHD)
179
How is the most common form of SCID inherited?
X-linked
180
How is the autosomal form of SCID inherited?
Autosomal recessive
181
Treatment for SCID:
HSC transplantation
182
X-linked Agammaglobulinemia is characterized by?
Failure of B cell maturation
| Marked decrease of B cells in circulation
183
How does XAG present?
Appears around 6 months of age after maternal antibodies are gone
Starts with recurrent bacterial infections
Almost always caused by: H. influenzae, S. pneumoniae, and S. aureus
184
What else is XAG susceptible to?
Enterovirus and Giardia lamblia
185
Treatment for XAG?
Replacement therapy with immunoglobulins
186
DiGeorge Syndrome is characterized by:
T cell deficiency due to failure of the 3rd and 4th pharyngeal pouches development
187
Common presentation/symptoms of DiGeorge:
Lack of T cell mediated immunity
Hypocalcemia
Congenital defects of heart and vessels
Mouth, ear facies
188
Bare Lymphocyte Syndrome
```
Mutations in transcription factors required for class II MHC molecules
B cells don't receive proper signaling
Leads to combined immunodeficiency
```
189
Hyper IgM Syndrome is caused by:
```
CD40/CD40L mutation
Most people (70%) have the X-linked form
```
190
What bacterial infection are patients with Hyper IgM susceptible to?
Pneumocystis jiroveci - pneumonia
191
Common Variable Immunodeficiency
Common feature is low levels of immunoglobulins
| But they will have normal levels of B cells (these areas may be hyperplastic)
192
Isolated IgA Deficiency
Occurs in about 1 in 600 European descent
Have extremely low levels of IgA
Most people are asymptomatic
Symptomatic people have recurrent sinopulmonary infetions
193
Overall defect of Isolated IgA deficiency:
Impaired differentiation of naive B cells to IgA producing plasma cells
194
What causes X-linked Lymphoproliferative Syndrome?
Inability to eliminate EBV leading to a fulminant infectious mononucleosis and development of B cell tumors
195
XLS is due to a mutation in which protein?
SLAM-associated protein (SAP)
| SLAM = signaling lymphocyte activation molcule
196
How is Wiskott-Aldrich characterized?
X-linked disease
Thrombocytopenia, eczema, recurrent infections
Mutations in the WASP gene/protein
197
How is Wiskott-Aldrich treated?
HSC transplantation
198
What are the symptoms of Ataxia Telangiectasia?
Abnormal gait, spider veins, neuro deficits, tumors, immunodeficiency
Defective isotype switching - primarily IgA and IgG2
Mutated protein is called ATM
199
Common causes of secondary immunodeficiency?
HIV, radiation/chemo, leukemias, malnutrition, removal of spleen, drugs or severe infection
200
How does radiation/chemo cause secondary immunodeficiency?
Decreased bone marrow precursors for leukocytes
201
How does malnutrition cause secondary immunodeficiency?
Metabolic derangments inhibit lymphocyte maturation
202
How does removing the spleen cause secondary immunodeficiency?
Decreased phagocytosis
203
What is the most common secondary immunodeficiency?
AIDS
204
Dominant mode of transmission for HIV/AIDS?
Sexual Transmission
205
How is sexual transmission enhanced?
By the presence of STIs
206
How is HIV passed on between mother and child?
1. In utero
2. During delivery
3. After birth by breast milk
207
Which strains of HIV are more common geographically?
HIV-1: US, Europe, Central Africa
| HIV-2: West Africa, India
208
HIV virus core contains:
p24 (major capsid protein)
p7/p9 (nucelocapsid protein)
Two copies of viral RNA
Three viral enzymes (protease, reverse transcriptase, and integrase)
209
What is the viral core surrounded by?
p17
210
What studs the viral enveope?
Two glycoproteins: gp120, gp41
211
HIV-1 Genome contains which three important genes typical of retroviruses?
gag, poly, and env
212
Two major targets of HIV?
Immune system and the central nervous system
213
What is considered the hallmark of AIDS?
Profound immune deficiency, primarily affecting cell-mediated immunity
214
What molecule does HIV use to infect cells?
CD4 molecule (on many cells)
215
What is the importance of CCR5 and CXCR4?
HIV has two strains:
CCR5: used by the R5 strains, which are M-tropic
CXCR4: used by X4 strains, which are T-tropic
216
Polymorphisms in CCR5 can lead to...?
Resistance of the HIV infection - happens in 1% of the white population
217
In 90% of HIV cases, which strain is dominant?
R5 strain; X4 will accumulate gradually over time though
218
Virus in quiescent cells versus dividing cells:
Q: cDNA will stay in the cytoplasm
D: cDNA circularizes and moves to the nucleus, incorporates into host DNA
219
Why is HIV ineffective at infecting naive T cells?
Naive T cells still have the APOBE3G enzyme activated which inhibits DNA replication of the HIV virus
This becomes inactivated in mature T cells
220
What accessory gene in HIV allows it to inactivate APOBE3G?
Vif gene - binds to the enzymes and degrades it
221
How can the HIV virus be activated again after being in a latent phase?
Stimulation by antigen or cytokine will release NF-kB and can activate it
HIV is capable of activating these mechanisms on its own
222
What causes the depletion of CD4+ T cells in HIV?
Mainly the direct cytopathic effects of the replicating virus
223
What are the giant cells formed in HIV called?
Syncytia - specific to the T-tropic, X4 strain
224
If HIV activates the inflammasome pathway, what happens next?
Cell undergoes pyroptosis
225
What percentage of CD4+ T cells in the lymph nodes are latently infected?
0.05%
226
What are other big effects caused by HIV?
Lymphopenia
Decreased T-cell function
Polyclonal B activation
Altered Monocyte/Macrophage functions
227
What is the vpr gene responsible for?
Allowing the HIV-1 strain to infect and multiply in terminally non-dividing macrophages
228
Why are macrophages considered reservoirs for HIV?
Because they don't die once they're infected - allow HIV to replicate within them
229
Why are follicular dendritic cells potential reservoirs?
These can trap the virus once it has been coated with antibodies and remain in the germinal centers of lymph nodes
230
What does polyclonal activation of B cells lead to?
Germinal center B cell hyperplasia
231
What are the predominant cell type in the brain once infected with HIV?
Macrophages/microglia
232
Acute retroviral syndrome is caused when?
Presents during the initial spread of the virus along with the initial host response
See a lot of non-specific, flu-like symptoms
Appears in 40-90% of those infected
Occurs about 3-6 weeks post infection
Resolves spontaneously 2-4 weeks later
233
How can the extent of viremia be measured?
Levels of HIV-1 RNA - the lower the viral load, the better
234
According to the CDC, when is it considered AIDS?
No matter the viral load, if there is a constitutional (widespread) disease, neuro disease, or neoplasm, it is considered AIDS
235
When there are few or no clinical manifestations, it's called:
Clinical Latency Period
236
Mechanisms HIV uses to avoid immune response:
Switch between CCR5 and CXCR4
Destroy CD4+ T cells
Antigenic variation
Down regulate Class I MHCs
237
Without treatment, how long before HIV becomes AIDS?
7-10 years
238
What is the most common presenting symptoms of AIDS?
Pneumonia caused by Pneumocystis jiroveci
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Most common fungal infection in AIDS?
Candidiasis
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Which parasite is responsible for CNS lesions?
Toxoplasma gondii
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What doe the JC virus cause?
Multifocal leukoencephalopathy
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What are some of the oncogenic DNA viruses?
Kaposi sarcoma
EBV --> B cell lymphoma
HPV --> cervical and anal carcinoma
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What is the mechanism behind AIDS patients developing Kaposi Sarcoma?
Caused by the KSHV or HHV8 virus
Shows proliferation of spindle shaped cells
Produces a cyclin D homologue
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What other diseases are linked to Kaposi Sarcoma?
Primary effusion lymphoma
| Multicentric Castleman disease
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Lymphoma and AIDS prevalence
5% of AIDS patients will present with lymphoma
| another 5% will develop it at some point
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Two mechanisms behind developing lymphoma after HIV infection:
1. Unchecked proliferation of B cells after profound T cell depletion --> primary effusion lymphoma
2. Germinal center B cell hyperplasia during early HIV infection - not associated with EBV or KSHV
- caused by activation-induced deaminase (AID)
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Agressive B cell tumors that may occur:
Burkitt lymphoma
Diffuse large B-cell lymphoma
Both are associated with MYC and BCL6
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Hodgkin Lymphoma
B cell tumor associated with pronounced tissue inflammation
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Oral Hairy Leukoplakia
EBV driven squamous cell proliferation of the oral mucosa
Appears as white patches on the side of tongue
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HAART stands for:
Highly active antiretroviral therapy
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After using HAART, what happens to T cells?
They can return to normal levels after a few years of treatment
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Complications with HAART treatment:
1. Some people develop IRIS = immune reconstitution inflammatory syndrome
2. Side effects: lipoatrophy (loss of facial fat), lipoaccumulation (centrally), insulin resistance, elevated lipids
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Main mechanism behind amyloidosis:
Extracellular deposits of misfolded fibrillary proteins are responsible for tissue damage
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What do the fibrils bind to?
Proteoglycans and glycosaminoglycans like heparan sulfate and dermatan sulfate
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AL (amyloid light chain) proteins are made up of:
Complete immunoglobulin light chains or amino-terminal fragments of light chains
Most are lambda light chains, but can be kappa
Secreted by plasma cells
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AA (amyoid-associated) proteins are made up of:
Unique non-Ig proteins made by the liver
Derived from a larger precursor, SAA which causes secondary amyloidosis
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Beta-amyloid portein (AB) is found in which disease?
Alzheimer's
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Rarer amyloids include:
TTR (transthyretin): mutant forms cause familial amyloidosis, normal forms can cause senile forms
B2-microglobulin: component of MHC Class I, identified as AB2m in amyloidosis
Prion proteins: disease of the CNS
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Primary Amyloidosis is associated with?
Plasma cell disorders (like multiple myeloma) - due to clonal proliferation
Major amyloid protein: AL
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Secondary/Reactive Systemic Amyloidosis is associated with?
Chronic inflammatory conditions; often seen with RA
| Major amyloid protein: AA
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Hemodialysis Amyloidosis is associated with?
Chronic renal failure
| Major amyloid protein: AB2m
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Familial Mediterranean Fever
Autosomal recessive, autoinflammatory syndrome caused by excess IL-1
Major amyloid protein: AA
Found in Armenian, Sephardic Jews, Arabs
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In other heredofamilial amyloidosis, what is the major amyloid protein?
Mutant TTRs
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Localized Amyloidosis?
Major amyloid protein: AL
265
Endocrine amyloid is associated with?
Endocrine tumors, specifically medullary carcinoma
| Amyloid proteins are derived from polypeptide hormones
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Amyloid of Aging (2 types)
1. Senile systemic amyloidosis: deposition of amyloid in the elderly (70s/80s), involvement of the heart
Amyloid is derived from normal TTR
2. Cardiac amyloidosis: another form that affects the heart, but amyloid comes from a mutant TTR
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Amyloid is most often deposited where?
In the glomeruli of the kidney
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Differences in deposition of the spleen:
1. Sago spleen = splenic follicles
| 2. Lardaceous spleen = walls of splenic sinus
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Other organs affected in amyloidosis:
Macroglossia - enlarged tongue
Carpal ligament in hemodialysis patients
Liver - normal functioning by may be enlarged
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Most common sites biopsied for amyloidosis:
Kidney, rectal, or gingival tissues
