BMS 545 Immunology - November 15, 2024 PDF

WELCOME- BMS 545 IMMUNOLOGY NOVEMBER 15, 2024   Office hours:  Tues. 4-5 pm (virtual)  Thurs. 4-5 pm (in- person, 316J) ANNOUNCEMENTS  DITKI due Monday 11/18 by 12:59 pm...

WELCOME- BMS 545 IMMUNOLOGY NOVEMBER 15, 2024   Office hours:  Tues. 4-5 pm (virtual)  Thurs. 4-5 pm (in- person, 316J) ANNOUNCEMENTS  DITKI due Monday 11/18 by 12:59 pm  DITKI Blood Groups- ABO & Rh  THE REST OF THE SEMESTER (ALL MODULE 4)  11/15- Secondary Immunodeficiency (Asynchronous). Research Days 1-4 pm  11/18-Transplantation & Immune Pharmacotherapy  11/20-Transplantation & Immune Pharmacotherapy & Cancer  11/22- Cancer & Tumor Immunity  11/25- Hypersensitivity (Asynchronous- Enjoy Thanksgiving break)  11/27-11/29- Thanksgiving break  12/2- Autoimmune Disorders  12/4- “What’s Wrong with Me?” Case Study  12/6- Final Immunology debrief:The Well Patient  LEARNING OBJECTIVES  Provide examples of immune evasion that can lead to infection despite a functioning immune response (e.g. genetic variation, mutation, antigenic variation, latency, etc.)  Define & provide examples of antigenic drift and shift  Differentiate primary and secondary immunodeficiencies  Describe how environmental triggers, like infections can lead to secondary immunodeficiencies  Illustrate the origins of secondary immunodeficiency disorders & give an example of each  Outline the steps of the life cycle of HIV & define key clinical terms & proteins  Describe the basics of how antiretroviral drugs work & what clinical latency means  Define & provide examples of BnAbs Evasion and subversion of the immune system by pathogens 13-1 Genetic variation within some species of pathogens prevents effective long-term immunity Figure 13.1 Protective immunity against Streptococcus pneumoniae is serotype-specific  Strains, or serotypes, of S. pneumoniae have antigenically different capsular polysaccharides  Antibodies against capsular polysaccharides opsonize pathogen (phagocytosis)  A person infected with one S. pneumoniae serotype clears infection with type- specific antibody  This type-specific antibody provides no protection from a subsequent infection with a different S. pneumoniae serotype  Clearing this infection requires a new primary immune response, directed specifically at antigens of second serotype Evasion and subversion of the immune system by pathogens 13-2 Mutation and recombination allow influenza virus to escape from immunity Antigenic drift- process by which point mutations in influenza virus genes cause alterations in the structure of viral surface antigens. This causes year- to-year antigenic differences in strains of influenza virus Antigenic shift- process by which influenza viruses reassort their segmented genomes and change their surface antigens radically. New viruses arising by antigenic shift are the usual cause of the influenza pandemics Figure 13.2 Evolution of new influenza variants by antigenic drift *Like hemagglutinin, neuraminidase (not shown) is also subject to antigenic drift  During infection with influenza strain V, person P produced antibodies against various epitopes of viral hemagglutinin- Some are neutralizing (green); others are not (blue)  Later in flu season, when person P is again exposed to strain V, neutralizing antibodies prevent cells from being infected  On infecting person Q, strain V mutates to strain V*, which differs from V by an amino acid substitution (yellow) in viral hemagglutinin which eliminates epitope recognized by neutralizing antibodies elicited by strain V  Consequently, strain V* influenza virus can infect cells of person P without hindrance from V-specific antibodies  To clear this 2nd infection, P must make a primary immune response of neutralizing antibodies specific for strain V* Figure 13.3 Evolution of new influenza variants by antigenic shift Human (red) & avian (blue) influenza viruses can also infect pigs, which serve as secondary hosts  In pig cell infected with human + avian viruses, RNA genome segments sorted to produce various recombinant viruses  Avian hemagglutinin is antigenically very different from hemagglutinins of influenza currently infecting humans, including the one that infected the pig cell  Recombination of avian & human RNA gives a virus that infects human cells & has new form of hemagglutinin  Humans are highly susceptible to recombinant virus because they don’t have antibodies to prevent infection  Because entire human population is vulnerable to recombinant virus, it’s capable of producing a pandemic Evasion and subversion of the immune system by pathogens 13-3 Trypanosomes use gene conversion to change their surface antigens Figure 13.4 Antigenic variation by African trypanosomes allows them to escape from adaptive immunity The top three panels show the genomic organization of VSG genes  Top: VSGa (red box) in the expression site, & other VSG genes are inactive (other color box)  2nd: gene conversion replaces VSGa with VSGb at expression site (yellow box)  3rd: VSGc replaces VSGb at expression site (blue box) The bottom panel shows how the person’s parasite load (red, yellow, blue, & green lines) coevolves with that person’s antibody response (dotted black lines)  In 1st week, trypanosomes expressing VSGa proliferate (red line), but as anti-VSGa antibody is produced, #s decline  Selection pressure imposed by anti-VSGa antibody enables parasites expressing VSGb to proliferate during 2 nd week of infection (yellow line), & then decline when anti- VSGb antibody is made  In 3rd week, parasites expressing VSGc dominate  In 4th week, parasites expressing VSGd to dominate, etc., until patient dies from accumulated damage caused by chronic inflammation Evasion and subversion of the immune system by pathogens 13-4 Herpesviruses persist in human hosts by hiding from the immune response Figure 13.7 Persistence and reactivation of herpes simplex virus infection  Initial infection around lips is cleared by immune response, & while healing, is manifested as cold sores  Meanwhile, Herpes Simplex virus (small red dots) enters sensory neurons, e.g. trigeminal ganglion that innervates the lips, where it persists in a latent state  Later, stress can cause virus to leave neurons & reinfect epithelial cells  This reactivates immune response & causes cold sores (active phase)  During this active phase, virus can pass from one person to another Evasion and subversion of the immune system by pathogens 13-8 Subversion of IgA by bacterial IgA-binding proteins Figure 13.9 Evasion of IgA-mediated defense by a bacterial superantigen  Upper panel: combination of specific IgA & FcαRI on phagocytes causes elimination of bacteria that cross a mucosal barrier & infect underlying tissue  Lower panel: this mechanism for disposing of bacteria is thwarted by staphylococcal superantigen- like protein 7 (SSLP7) of S. aureus  By binding to both C5 & Fc region of IgA, SSLP7 prevents IgA from binding to FcαRI or activating complement-mediated killing of bacteria (not shown)  Superantigen- a molecule that, by binding non- specifically to MHC class II molecules and T-cell receptors, stimulates the polyclonal activation of T cells  FAILURE OF THE IMMUNE SYSTEM = REDUCED ABILITY TO RESIST INFECTION  Immunodeficiencies- caused by defects in components of immune system 1. Primary immunodeficiency disease- disease in which there is a failure of immunological function as a result of a defect in one or more genes encoding components of the immune system; Usually genetic, but can be result of randomly occurring errors in development  Most become apparent at ~6 months old, when maternally derived antibodies begin to disappear 2. Secondary immune deficiencies- caused by environment; e.g. infection, therapeutic treatments, cancer, & malnutrition  May occur at any time of life, depending on when the exposure to the causative factor(s) occurs  Both characterized by recurrent or chronic infections, inability to clear infectious agents after standard antibiotic therapy, unusual infectious agents Chapter Opener  SECONDARY (ACQUIRED) IMMUNE DEFICIENCIES  Arise from environmental exposures & may occur at any time of life, depending on when exposure occurs.  Environmental factors that can induce immune deficiencies  Physiologic sequelae- ex. malnutrition  Therapeutic treatment  Cancer  Lymphocytes & monocytes that are malignant (lymphomas & leukemias) can crowd out normal hematopoietic cells  Infection- HIV Figure 13.20 The human immunodeficiency virus (HIV)  HIV is a retrovirus that causes a slowly progressing chronic disease  Retroviruses use reverse transcriptase enzyme to break the central dogma of molecular biology to go from RNA > DNA  Central dogma= DNA>RNA>protein  HIV infects CD4 T cells, monocytes/ macrophages, & dendritic cells Figure 13.21 The genes and proteins of HIV-1 and HIV-2  HIV-1 & HIV-2 have RNA genomes each consisting of nine genes flanked by long terminal repeats (LTRs)  Distinguishing HIV-1 & HIV-2 are the vpu & vpx genes, respectively  Several viral genes are overlapping & are read in different frames  Others encode large polyproteins that after translation are cleaved to produce several proteins having different activities  gag, pol, & env genes are common to all retroviruses, & their protein products are components of the virion  Acquired immune deficiency syndrome 13-22 Genetic deficiency of the CCR5 co-receptor for HIV confers resistance to infection (CCR5Δ32 mutation) Figure 13.23 The life cycle of HIV in human cells 1. gp120 envelope protein of HIV binds to CD4, enabling gp120 to also bind a co- receptor (CCR5 or CXCR4) 2. Binding releases gp41, causing fusion of viral envelope with plasma membrane & release of viral core into cytoplasm 3. RNA genome is released & reverse transcribed into double-stranded cDNA 4. DNA migrates to nucleus with viral integrase & integrates into genome as a provirus 5. Activation of T cell causes low-level transcription of provirus into mRNA that directs synthesis of early proteins Tat & Rev 6. Tat & Rev change pattern of provirus transcription to produce mRNA encoding protein constituents of virion & RNA molecules corresponding to HIV genome 7. Envelope proteins travel to plasma membrane, where other viral proteins & viral genomic RNA assemble into nucleocapsid Yes, there will be a question on this 8. New virus particles bud from cell, acquiring their lipid envelope & envelope glycoproteins Figure 13.24 After infection with HIV there is a gradual extinction of CD4 T cells  # of peripheral blood CD4 T cells (green line)  Opportunistic infections & other symptoms become more frequent as CD4 T-cell count falls, starting ~500 cells/μl; disease enters symptomatic phase  When CD4 T-cell counts