Week1 final review Flashcards
• TLR3
on cell surface or endosome surface recognizes dsRNA
• TLR3 binds dsRNA → leads to phosphorylation of IRF3 thru kinases→ enters the nucleus as a dimer and activates transcription → IFN-beta transcribed/produced
IRF3
• IRF3 and NFkB both act as transcription factors for the production of IFN-beta
NFkB
• IRF3 and NFkB both act as transcription factors for the production of IFN-beta
first responders to cytokines
neutros
type 1 vs 2 interferons
- Type 1 interferons (IFN-alpha and IFN-beta) are produced by infected cells
- Type 2 interferons (IFN-gamma) are released by Th1 cells
Cluster of Differentiation (CD) Molecules
- primarily used for identification of subsets of cells based on surface molecules – immunophenotyping
- can be receptors or ligands – i.e. some have functions in signaling and some serve as adhesion molecules
- CD45+ = all leukocytes
- CD45+, CD3+ = all T cells (CD3 is the T cell coreceptor)
- CD45+, CD3+, CD4+ = T helper Cells (CD4 is MHC II coreceptor)
- CD45+, CD3+, CD8+ = Cytotoxic T cells (CD8 is MHC I coreceptor)
• Divisions of node into areas
• Cortex = lymphoid tissue supported by a reticular fiber meshwork
o Numerous lymphocytes and lymphatic nodules with germinal centers
• Nodules are transitory – have tail which extends into medulla as medullary cords
o Stromal cells
• Medulla = lymphoid tissue supported by a reticular fiber meshwork and stromal cells
o Contains medullary cords and medullary sinuses
o Contains numerous small lymphocytes, differentiating & mature plasma cells, macrophages
• Division of cortex into areas
• Superficial cortex – located between capsule and outer limits of germinal center
o Contain a majority of B-cells
• Mid-cortex – area containing primarily the germinal centers
o Contain a majority of B-cells, together with other cells of the germinal center
• Deep cortex (paracortex) – area between germinal centers and medullary cords
o Contain a majority of T-cells – extend into the area between the nodules of the superficial and mid-cortex, and also into the medulla
o Lymph flow through lymph node
- Afferent lymphatic vessels
- Subcapsular (marginal) sinus
- Trabecular (peritrabecular) sinus
- Paracortical (subcortical) sinus
- Medullary sinus
- Efferent lymphatic vessel
o Blood flow through lymph node
- Arterial vessels (hilum)
- Trabecular vessels
- Arterioles and capillaries
- Post-capillary venules
o Outer cortex (superficial and mid) – lined by simple squamous endothelium
o Deep cortex (paracortex) – lined by simple cuboidal endothelium (HEV’s = high endothelial venules)
• HEV’s = site of passage of T and B cells from blood vessels into lymphatic tissue
• Re-circulate via efferent lymphatics back into blood vascular system
• Thymectomy = depletion of lymphocytes from deep and mid-cortex
o HEV endothelium reverts to simple squamous - Venous vessels (hilum)
Parvovirus B19 – “Fifth Disease”
• General features: linear ssDNA (-), small (5,000 nucleotides), non-enveloped, icosahedral
• Tropism: humans exclusively – erythroid progenitor cells, blood group P antigen
o Some people are P-antigen deficient and innately immune to parvovirus infection
o Replication occurs in erythroid progenitors; NS1 (viral protein) induces erythroid apoptosis
• Transmission: respiratory
• Clinical presentation: fifth disease – erythema infectiosum – macular rash and arthralgia, “slapped cheek” appearance
• Dx:
o High-titer B19V blood – screen by nucleic acid amplification technology (qualitative PCR)
o Detectable B19V IgM antibodies in immunocompetent patients
• IgM can be detected at time of rash in erythema infectiosum
• IgM can be detected by 3rd day in patients showing transient aplastic crisis
o Detectable B19V IgG antibodies by 7th day of illness & persists throughout life
• Tx: supportive (no antiviral, no vaccine for B19) – IV Ig in immunocompromised individuals
• Transient aplastic crisis can occur when:
o Patients have pre-existing hemolytic disorders, hemoglobinopathies, red cell enzymolopathies, hemolytic anemias
o Any situation where patients rely on high turnover of RBCs (ex. chemo patients)
• Other conditions caused by parvovirus: chronic anemia/pure red cell aplasia; hydrops fetalis (fetal loss)
o Rarely: hepatitis, vasculitis, myocarditis, glomerulosclerosis, meningitis
Colorado Tick Fever Virus
• General features: linear dsRNA, non-enveloped, icosahedral
o Uses negative strand of its genome for transcription and as a template for replication of positive strand
• Tropism: erythrocytes
o Animal vectors – rocky mountain wood tick, small mammals
o Geography: Rockies, West Coast; Season: Spring, Summer, May-September (peaking in June)
• Clinical Presentation: fever (sometimes biphasic), chills, body aches, lethargy/malaise
• Dx:
o Culture in reverse-transcriptase PCR from blood or CSF
o Hx, detection of viral RNA, detection of IgM
• Tx: supportive care
• Other conditions: meningitis, encephalitis
o Dx: RT-PCR, blood culture, non-contrast head CT, LP, MRI
o Tx: ceftriaxone empirically and ABx can be further differentiated with culture
HHV-4 (Epstein Barr Virus, EBV)
• General Features: dsDNA (gamma-1 herpes virus), enveloped, icosahedral
• Tropism: lytic cycle in epithelial tissue, latent infections in B-cells
o Gains entry to B cells by contacting CD21 on surface of B-cells
• Directly in tonsillar regions or indirectly through contact with epithelial cells
• Malignancies associated with EBV:
o Burkett’s lymphoma, Anaplastic nasopharyngeal carcinoma, Hodgkin’s disease, Lymphomatoid granulomatosis
o EBV oncogene LMP1 is a homolog of a normal cellular protein = CD40 (tumor necrosis factor subtype)
• LMP1 activates epidermal growth factor receptor transcription factors
o EBV oncogene EBNA3C is essential for EBV’s ability to cause B cell transformation
• EBNA3C affects control of G1→S phase checkpoint by inducing epigenetic silencing of BIM (pro-apoptotic)
• Clinical Presentation: “classic triad” of infection mononucleosis (IM) sx
o Mild fever (10-14 d), severe acute pharyngitis (3-5 d), lymphadenopathy (post cervical lymph nodes)
• Dx:
o Monospot test – detects IgM antibodies produced by B cells
o VCA (viral capsid antigen)-IgM appears first during an infection and dissipates within 4-6 wks
o VCA-IgG appears during acute phase of EBV infection and persists throughout life – result of adaptive immune system
o Atypical lymphocytes (deformed nuclei & dark-rimmed cytoplasm) of Downey cells in a blood smear is dx for EBV
HHV-5 (Cytomegalovirus, CMV)
• General Features: dsDNA, enveloped, icosahedral
• Tropism:
o Systemic Infections: epithelial cells, endothelial cells, smooth muscle cells, macrophages, neurons
o Latent infections: virus establishes lifelong latency or persistence in CD34 myeloid progenitor cells (and others)
o Gains entry to host and establishes infection by:
• 2 membrane glycoprotein complexes (gB and gH-gL dimer) mediate attachment and invasion of host cells
o Evades host immune response:
• CMV has a specific mechanism of “immune evasion” that allows it to maintain the latent state for long periods
• CMV encodes several microRNAs – bind to and prevent translation of cell’s mRNA for class I MHC protein
• Assembly of MHC I-viral peptide complex is unstable → viral antigens not displayed on cell surface and killing by cytotoxic T cells does not occur
• Transmission: congenitally and by transfusion, sexual contact, saliva, urine, or transplant
• Clinical Presentation:
o 20% of infants infected with CMV during gestation show manifestations of cytomegalic inclusion disease
• Microcephaly, seizures, deafness, jaundice, purpura (blueberry muffin)
• Hepatosplenomegaly is very common
o In immunocompetent adults, CMV can cause heterophil-negative mononucleosis
• Fever, lethargy, presence of abnormal lymphocytes in peripheral blood smears
o Systemic CMV infections – pneumonitis, esophagitis, hepatitis – occur in immunocompromised individuals
• Dx:
o Enzyme linked immunoassays for pp65 within leukocytes (part of nucleocapsid of CMV)
o Presence of owls eye cells on blood smears
• Other conditions: retinitis, deafness, hepatitis, CMV acalculous cholecysitis
• Tx:
o Uncomplicated systemic: supportive
o Severe systemic congenital CMV: ganciclovir
o Acyclovir is not effective for CMV infections because there is no TK in the virus
HHV-6; HHV-7 (exanthum subitum)
• General features: dsDNA (beta herpes virus subfamily, genus Roseolovirus), lipid envelope, icosahedral
• Tropism: CFU-GEMM (hematopoietic stem cell), monocyte, peripheral blood mononuclear (neutrophil, macrophage, eosinophil, basophil, T & B cells), epithelial cells
• HHV-7 vs. HHV-6
o HHV-7 has narrower tissue tropism – CD4+ T cells, epithelial cells of salivary glands, cells in lungs and skin
o HHV-6 infects CD4+ T cells, B cells, NK cells, monocytes, macrophages, epithelial cells, and neural cells
• Clinical Presentation: most cases of exanthema subitum (sixth disease or roseola infantum) occur in infancy and early childhood
• Dx: unique course of disease
o Faint pink/rose colored, nonpruritic, 2-3 mm morbilliform rash on trunk which develops after fever (72 hrs) resolves
• Tx: ganciclovir and foscarnet – definitive evidence of clinical response is lacking
• Other conditions: mononucleosis, pityriasis rosea
o In immunocompromised: encephalitis, pneumonitis, synctitial giant-cell hepatitis, and disseminated disease
• Tx: ganciclovir, foscarnet, cidofovir
HHV-8 (Kaposi Sarcoma Herpes Virus, KSHV)
• General Features: dsDNA, enveloped, icosahedral
• Malignancies: Kaposi Sarcoma
o KSV’s vFLIP is a homolog of FLIP (cellular protein that regulates apoptosis)
o KSV’s vBcl-2 is a homolog of Bcl-2 (regulates apoptosis)
o KSV’s vGPCR is a homolog of GPCR (regulates cell fate)
o KSV’s vCyclin is a homolog of Cyclin (regulates apoptosis)
• Tropism: B cells
o People affected: immunocompromised
• Tx: target lytic phase (prevent reinfection only)
o Ganciclovir – chain terminator
o Cidofovir – inhibitor of viral DNA polymerase
o Foscarnet – structural mimic of anion pyrophosphate that selectively inhibits the pyrophosphate binding site on viral DNA polymerases at concentrations that do not affect human DNA polymerases
HTLV-1; HTLV-2 (Human T-Cell Lymphotrophic Virus)
• General Features: + ssRNA with reverse transcriptase, enveloped, icosahedral
• Tropism: T cells
• HTLV-1 vs. HTLV-2
o HTLV-1 causes T-cell Leukemia and HTLV-1 associated myelopathy/tropical spastic paraparesis
o HTLV-2 is nonpathogenic, more common in Caribbean region, Eastern South America, Western Africa, Southern Japan
• Binds host cell gp46 and enters through fusion with cell’s plasma membrane
o To become a provirus, HTLV has to integrate into the host cell’s DNA
o HTLV provirus expresses its genes by Tax-induced viral gene transcription and Rex-induced translation of viral mRNA
o HTLV causes T cell leukemia
• Tax (HTLV transcription factor) contributes to pathogenesis by binding CREB, CREM, NFKB, and NSF
• Host genes that are upregulated: NFkB, IFN-I, IFN-beta, TBK1, and IKKE
• Host genes that are down-regulated: p53, DLG, IkB degradation
• Contributes to transformation by activating cellular promoters (surface receptors, cytokines) and signaling cascades (Jak/STAT, PI3Kinase, JNK) → upregulated protein/gene expression
• Malignancies
o Acute T-cell Lymphoma (leukemia) – occurs in 2-4% of people infected with HTLV-1
• Clinical presentation: malaise, night sweats, fever, cachexia, adenopathy
o HTLV-1 Associated Myelopathy (HAM) aka tropical spastic paraparesis
• Infected T cells are trafficked into the perivascular and parenchymal areas of the spinal cord → astrocytosis and inflammation of spinal gray and white matter → progressive demyelination
• Clinical presentation: gait disturbance, stiffness/weakness in legs, back aches, weak bladder, constipation
HIV-1; HIV-2
• General Features: +ssRNA (retrovirus), enveloped, icosahedral
• Tropism: CD4+ T cells primarily – also macrophages and dendritic cells – key target molecules: CD4, CCR5, CXCR4
• HIV-1 vs. HIV-2
o HIV-2 has a lower transmissibility and less potential to progress to AIDS
o HIV-1 is found worldwide; HIV-2 is more confined to West Africa
• In a healthy person, there are 500 to 1200-1,500 cells of CD4 positive T cells per microliter (cubic mm) of blood
o Below 500 per cubic mm = immunocompromised; below 200 cells per cubic mm = AIDS
• Role of CD4+ T cells in immune system: mediate inflammation, recruit B cells/humoral response, decide when “enough is enough” to shut down immune response
o If CD4+ T cells are depleted – lose a key piece in immune response
o Cause of death of HIV/AIDS patients is not directly due to HIV – patient will pass from separate, AIDS-related DZ to which they have a limited immune response
• Tx:
o Zidovudine (Retrovir) – thymidine analog (nucleoside reverse transcriptase inhibitor), blocks RT at activation site
o Efavirenz – non-nucleoside reverse transcriptase inhibitor (NNRTI), binds RT far from active site
o Raltegrovir – entry inhibitor, inhibits catalytic activity of HIV integrase
o Ritonavir – HIV protease inhibitor
o Maroviroc – chemokine receptor 5 antagonist, HIV entry inhibitor
• Dx: rapidly by rapid antibody/antigen test (ELISA) → confirmed by Western Blot
o HIV + patients immune status monitored by CD4 test and RT PCR viral load tests
Ebola Hemorrhagic Fever
• General Features: non-segmented (-) ssRNA, enveloped, helical
o Viral genome can be used as a template for translation of viral proteins
• In order to make new copies of the genome, a positive strand must first be synthesized
• Tropism: many cell types – replicates in monocytes, macrophages, and dendritic cells
• Clinical Presentation
o Early clinical signs: fever, myalgia, general malaise, chills – often confused with malaria or dengue in tropical climates
• Initial period followed by flu-like sx accompanied by GI sx
• Severe cases → maculo-papulary rash, petechiae, conjunctival hemorrhage, epistaxis, melena, hematemesis, shock, encephalopathy
o End-stage disease characterized by severe organ dysfunction, encephalitis, anuria, seizures, and death
• Tx: supportive care
o Aggressive replacement of fluids and electrolytes
o Oxygen and vasopressors used to maintain adequate bodily function
o Leukocytes enter venules
o Blood vessels in tissue – endothelial cells react to TNF- α released by macrophage → produce E-selectins
• Leukocytes enter venules → expanded area decreases flow through zone → slows down, rolls on surface across venule → leukocyte can bind to E-selectin in on surface of endothelial cell
• Cytokines (ex. IL-8) create stable interaction between leukocyte and surface of endothelial cell
• Endothelial cells make ICAM-1 – leukocytes have CR3/LFA-1 → interaction leads to migration of leukocyte into tissue
• Leukocyte rolling on surface of venule → tethering (E-selectin and CD-15) → adhesion (cytokines) → migration into tissue (ICAM-1, CR3/LFA-1)
o MHC II complex presented on surface of macrophage → can interact with CD4+ T cell
• Th1 → supplies IFN- ϒ to macrophages to turn them way up to the M1 state
o NF-κB
• Stimulation of TLRs by PAMPs & DAMPs initiates signaling cascades → activation of AP-1, NF-κB, & interferon regulatory factors
o NF-κB = “the Mother of all immune system transcription factors”
o Signaling results in the production of interferons (IFNs), pro-inflammatory cytokines, and effector cytokines that direct the adaptive immune response
• Activation of NF-κB which causes:
• Expression of pro-inflammatory genes
o Production of prostaglandins and other leukotrienes
o Production of interleukins and other cytokines
• Increased phagocytosis & synthesis of reactive O2 & N molecules in macrophages & neutrophils
• Increased efficiency of antigen presentation
• Three pathways of complement activation:
o Classical pathway (adaptive immunity)
• C1q binds to antigen:antibody complex. Cleaves and activates downstream complement components
• C5b binds to the membrane associated with the antigen:antibody complex which leads to the formation of the membrane attack complex
o Lectin pathway (innate immunity)
• Mannose binding protein bound to bacterial carbohydrates mimics C1q. Leads to the cleavage and activation of downstream complement components
• C5b binds to the membrane which leads to the formation of the membrane attack complex
o Alternative pathway (innate immunity)
• C3 is spontaneously cleaved or cleaved by C3b by serum proteases activated by bacteria
• C3b binds to bacterial and yeast cell walls and viral envelopes
• Bound C3b leads to the downstream activation of the complement components
o C3a, C4a, and C5a
- Chemotactic factors that increase directional migration of PMNs and macrophages
- Activate PMN and macrophage degranulation – release digestive enzymes and adhesion factors
- Cause mast cells and basophils to degranulate releasing large quantities of histamine
- Potency: C5a»_space;> C3a»_space;> C4a
o C3b and C4b
- Deposited on any surface with an exposed amine or hydroxyl, such as a bacteria cell
- Act as opsonins; further cleave C3
- When bound to host cells they are inactivated by decay-accelerating factor (DAF)
o C5b
- Binds to microorganisms or host body cells
- Acts as a focal point for the deposition of the membrane attack complex
- Body cells have protectin (CD59) and homologous restriction factor (HRF) to prevent the formation of the membrane attack complex
