41

BIO430 (Fach) / Lectures (Lektion)

All

Diese Lektion wurde von estoffel erstellt.

Lektion lernen

zurück  |  weiter 1 / 1

Anzeige
  • Genome facts - 3.2 billion base pairs - 20'000 protein coding genes - 99% identical to chimpanzees - 99.6% inter-individual identitiy--> remaining 0.4% makes a person unique
  • Locus Location of a gene/marker on the chromosome
  • Polymorphism - Variations in DNA sequences that are present in greater frequency than 1% in a population - have a weak effect or no effect at all - ancient and common
  • Mutation - Variations in DNA sequence that are present at a frequency less than 1% in a population - can cause gain of function and loss of function - recent and rare
  • SNPs - account for about 90% of all human genetic variations - around 50 million in total - difference to mutation: must occur in at least 1% of population
  • Gene markers Use of SNPs For common diseases, genetic association (stats-based) have performed better than genetic linkage (pedigree- based) 
  • Navarini: Acne pathogenesis - Signals were close to TGFβ-related gene
  • Population stratification - Populations are not homogenous- Most human variation is "within population" --> Reduced Power- Adds 'noise' to any allele frequency differences and may drown out a true signal of association- Leads to fewer true positives --> Confounding- a locus may appear associated via population stratification only- leads to more false positives
  • Checkpoint molecules - CTLA-4- PD1 - inhibit cell activity--> Inhibition of these "checkpoint" molecules may boost immune responses against tumor
  • Glioblastoma-associated immunosuppression - TGFβ - IL-10 - PGE - HLAG ...
  • Anzeige
  • What are humanized mice? Animals that carry human cells While human genes can be introduced into the murine germline (genetic engineering), human cells, tissue or organs need to be transplanted into the animals (xenotransplantation) 
  • RAG2-/- γc-/- mice - RAG1 and RAG2 are essential proteins to initiate V(D)J recombination  - Deletion of the common γ-chain reduces cytokine signaling, no NK cells 
  • NOD-scid γc-/- (NSG) mice Injection of stem cells into newborn mice - SCID mutation ‘deletes’ murine T and B cells- NOD mutation reduces innate immune functions- Deletion of the common γ-chain reduces cytokine signaling, no NK cells 
  • Eliminating NK cells - target common γ-chain
  • How to make humanized mice - Transplantation of mice with human hematopoietic stem/progenitor cells (HSC/HPC) instead of mature immune cells  - Inject human stem cells into newborn Nod-scid γc-/- (NSG) or Rag2-/- γc-/- mice 
  • Bone-Marrow/Liver/Thymus mouse (BLT mouse) Transplantation of human liver and thymus graft into adult NSG mice - SCID mutation ‘deletes’ murine T and B cells- NOD mutation reduces innate immune functions- Deletion of the common γ-chain reduces cytokine signaling, no NK cells
  • Diseases modeled in HIS mouse - HIV- Dengue virus- EBV- KSV
  • Cytotoxic T-lymphocytes - recognize tumor associated antigens (TAA) derived from cytoplasmatic proteins that are displayed bound to class I MHC molecules. - kill target cells by releasing toxic proteins or by activating death receptors on target cells. 
  • Ipilimumab CTLA4-Inhibitor - Used in advanced melanoma
  • Natural killer cells - Develop in the bone marrow - 10% of cells in the total peripheral mononuclear blood population- In humans, 2 subsets of NK cells: cytokine producers and killers  Functions:- Cancer Immunosurveillance - Reproduction: Establishment of placenta, Tissue remodeling - Allogeneic Stem Cell Transplantation- Control of infections (viral)- Control of the switch from innate to adaptive immunity  - Granule-dependent killing (perforin, granzyme)  - Engagement cell death receptors results in caspase-dependent apoptosis - Antibody-Dependent cellular cytotoxicity 
  • Chimeric antigen receptors (CARs) - Highly effective against refractory ALL CLL with 70-90% CRR!  But...- Hyperimmune activation – cytokine release syndrom- Cross reaction – killing of normal B cells 
  • IL-17A overexpression - overexpression in all tissues induces inflammation in body-lining tissues (epithelium of skin, lung, gut) - psoriasiform
  • Psoriasis - δγ T17 cells drive skin inflammation
  • GM-CSF - absolute requirement for T cell pathogenicity - elevated levels cause neurological deficits dominated by rotatory phenotype - not only necessary but also sufficient to drive neurological deficits
  • Dominant cells in tissue inflammation ALWAYS Myeloid cells (not lymphoid!)
  • Predisposing conditions for fungal infections - Primary or secondary immunodeficiency - Immunosuppression - Modern medical interventions
  • Resistant fungi - Aspergillus fumigatus - Candida auris
  • Candidiasis Immune Defects CD4 T cell defects--> mucocutaneous Candida infections--> IL-17 plays non-redundant role Phagocyte defects (e.g. neutropenia, CGD)--> invasive infections with Candida and Aspergillus IL-17 immunity and neutrophil response act complementary
  • Herpes viruses α: Herpes virus 1, 2, Varizella zoster β: CMV, HHV6/7 γ: Epstein-Barr, Karposi sarcoma
  • EBNA1 - binds to a replication origin (oriP) within the viral genome - sorting of viral episome during mitosis
  • Anzeige
  • LMP LMP1: mimics CD40 signaling LMP2: mimics BCR signaling
  • Münz conclusions EBV drives infected B cells through the physiological B cell differentiation process to gain access to the memory B cell pool for persistence. EBV ensures survival of infected B cells in the germinal center reaction, where infected B cells probably acquire mutations and become malignant. Only when EBV’s host B cell becomes a short-lived plasma cell after antigen stimulation of its B cell receptor the virus switches to lytic infection and leaves the cell.  All tumor associated EBV transcription programs are present in healthy carriers of the virus. Immune suppression or altered primary infection predisposes for EBV associated malignancies. Cytotoxic lymphocytes, NK and CD8+ T cells, control EBV. They expand during primary infection, they can be used for treatment of some EBV associated malignancies and primary immunodeficiencies that affect them result in uncontrolled EBV infection. 
  • IL-2 Trimeric receptor:- Stimulation via IL-2 receptor α (CD25)- low doses of IL-2-> Treg differentiation Dimeric receptor:- Simulation via IL-2 receptor β (CD122)- high doses of IL-2 --> CD8 and CD4, NK responses to solid and hematological tumors - IL-2 specific antibodies can amplify cell response
  • Adverse effects of IL-2 immunotherapy Vascular Leak Syndrome - e.g. pleural effusion
  • Epidemiologie TB Schweiz 30% Schweizer 30% Ausländische Arbeitgeber 20% Flüchtlinge
  • Tuberculosis in childhood - primary infection - higher risk for progression of disease - higher rate of extrapulmonary TB - identify adult source (spreader)
  • Diagnosis of tuberculosis - sputum - gastric aspirate (child) - body fluids - tuberculin skin test - blood tests: TB-SPOT, quantinterferon-TB Gold
  • Tuberculin skin test INDIRECT test; Based on cellular immune response - limited sensitivity in immunocomprimsed/HIV infected - false negative in active TB - no differentiation between infection and disease, NTM/TB/BCG - no treatment monitoring - booster effect - Diagnosis of latent TB relies on TST - Ability to predict active disease - Treatment of latent TB (diagnosed by TST) reduces the risk of disease by about 60% 
  • Myasthenia gravis - Immunopathology - Antibodies bind to the AChR (80-85%)- Complement-mediated destruction- Accelerated internalization and degradation - Blocked ACh-AChR binding - Anti-MuSK (10%): IgG4, do not fix complement
  • The thymus in myasthenia gravis The thymus is abnormal in most MG patients – Lymphoid follicular hyperplasia: 70%– Thymoma > 10%  - Muscle-like myoid cells express AChR in hyperplastic thymus glands and neoplastic cells in thymomas express AChR-, titin-, and ryanodine receptor-like epitopes - likely involved in initiation of the anti-AChR immune response 
  • Myasthenia gravis - Autoantibodies Anti-Acetylcholine antibodies- Sensitivity approx. 85% for generalized MG - rarely false positive - Nearly all thymomatous MG pts are positive - May be normal at symptom onset  Anti-striated muscle antibodies:- In 75-85% of patients with MG and thymoma- main clinical value in predicting thymoma in early-onset MG Anti-MuSK antibodies- In 50% of AChR-negative MG patients Anti-LRP4 antibodies

zurück  |  weiter 1 / 1