Responses to Extracellular Infection PDF 2024

November 2024 Responses to Extracellular Infection Dr. Patrick Walsh Class Year 1 ModuleBMF Title Responses to Extracellular Infection  IMMUNOLOGY LECTURES OUTLINE...

November 2024 Responses to Extracellular Infection Dr. Patrick Walsh Class Year 1 ModuleBMF Title Responses to Extracellular Infection  IMMUNOLOGY LECTURES OUTLINE TIME Barrier Immunity Physical barrier (Intro to Instant Imm lecture)Infection Mechanical barrier (Intro to Imm lecture) T H E W O R L D T O B E T T E R H E A LT H Chemical barrier (Intro to Imm lecture) Minutes- Hours Innate Immunity Cytokines (Intro to Imm lecture) Inflammation (Inn Imm lecture) Days-weeks Complement (Inn Imm lecture) Antigen Presentation (Inn Imm RCSI LEADING lecture) Response to Extracellular Inf Adaptive Immunity T cells – Cytotoxic and Help lecture (T cell lecture) Response to Intracellular Inf  LECTURE LEARNING OUTCOMES By the end of this lecture you should be able to: Using streptococci and helminths as an example, describe the immune response to extracellular infections T H E W O R L D T O B E T T E R H E A LT H Describe how innate immune cells detect extracellular infections Describe how antibodies help with elimination of extracellular infections Describe how B cell memory is established Outline conditions that cause hyposplenism Describe the clinical consequence and management of hyposplenism RCSI LEADING  IMMUNE RESPONSE IS REQUIRED AGAINST DIFFERENT TYPES OF INFECTION Viruses Extracellular Bacteria T H E W O R L D T O B E T T E R H E A LT H Intracellular Bacteria Fungi Protozoan Multicellular parasites RCSI LEADING  EXTRACELLULAR VS INTRACELLULAR T H E W O R L D T O B E T T E R H E A LT H Bacteria, Fungi, Viruses Bacteria Protozoa, Helminths Fungi RCSI LEADING Protozoa Need different types of response to fight different infections  EXAMPLES OF EXTRACELLULAR VS INTRACELLULAR Extracellular: bacteria/parasites that live and multiply outside of cells  Streptococci pyogenes T H E W O R L D T O B E T T E R H E A LT H  Staphlococcus aureus  Haemophilus influenza  Schistosoma mansoni Intracellular: organisms that invade a cell to survive/multiply/evade detection RCSI LEADING  Listeria monocytogenes Intra-  Mycobacterium tuberculosis vesicular  Viruses (truly intracellular)  COOPERATION BETWEEN INNATE AND ADAPTIVE IMMUNITY IS REQUIRED Macrophages and dendritic cells at site of infection; early line of T H E W O R L D T O B E T T E R H E A LT H defence in innate immunity B cells and existing circulating antibodies specific to outer coat proteins or lipids also important Antigen presentation to T cells  activation of T helper cells and RCSI LEADING cytotoxic T cells RCSI LEADING T H E W O R L D T O B E T T E R H E A LT H INFECTIONS RESPONSE TO EXTRACELLULAR OVERVIEW OF IMMUNE  INNATE IMMUNITY TO EXTRACELLULAR INFECTIONS Complement activation Phagocytosis T H E W O R L D T O B E T T E R H E A LT H Inflammatory response We saw all these during our Innate Immunity Lecture!!!! RCSI LEADING  COMPLEMENT ACTIVATION T H E W O R L D T O B E T T E R H E A LT H RCSI LEADING Classical pathway is activated by antibody recognition from previous infections Alternative pathway is activated by peptidoglycans in cell walls of gram positive and gram negative bacteria Lectin pathway Dr Chiara D e S a n t i , R e s p is o n s activated e t o E x t r a c e l l by u l a r bacteria Infections that express mannose on their surface  PHAGOCYTOSIS AND INFLAMMATION Phagocytosis is initiated by mannose receptors and complement receptors Killing of the microbes T H E W O R L D T O B E T T E R H E A LT H happens in the phagolysosome via reactive oxygen species (ROS) and nitric oxide (NO) Activation of innate immune cells cause production of inflammatory mediators: RCSI LEADING  TNF, IL-1, IL-6, IL-8, prostaglandin etc mediate inflammation  Instructive cytokines to guide  ADAPTIVE IMMUNITY TO EXTRACELLULAR MICROBES T Helper Cells T H E W O R L D T O B E T T E R H E A LT H (Adaptive Immunity – T cells lecture) Antibody production RCSI LEADING (Adaptive Immunity – B cells lecture)  SUMMARY OF EXTRACELLULAR BACTERIAL INFECTION T H E W O R L D T O B E T T E R H E A LT H RCSI LEADING The video has now been uploaded in the Moodle folder for extracellular infections RCSI LEADING T H E W O R L D T O B E T T E R H E A LT H STREPTOCOCCI IMMUNE RESPONSE TO  STREPTOCOCCI Gram positive aerobic bacteria Spherical T H E W O R L D T O B E T T E R H E A LT H Encapsulated Polysaccharide rich coat Releases toxins Strains include Streptococcus pyogenes and Streptococcus Streptococcus RCSI LEADING pneumoniae pneumoniae  MEDICAL CONDITIONS Most common Pharyngitis (strep throat) Skin Infections – Impetigo T H E W O R L D T O B E T T E R H E A LT H – Scarlet fever – Cellulitis More serious conditions toxic shock syndrome pneumonia necrotizing fasciitis RCSI LEADING  OVERVIEW OF IMMUNE RESPONSE TO STREPTOCOCCI Extracellular microbe Resident macrophages induce phagocytosis and T H E W O R L D T O B E T T E R H E A LT H inflammation Recruitment of neutrophils Antigen presentation to CD4+ T helper cells Antibody production by B cells RCSI LEADING  RECOGNITION AND ACTIVATION OF INNATE IMMUNITY gram positive bacteria (such as microbes streptococci) T H E W O R L D T O B E T T E R H E A LT H IL-1/TNF/IL-8 – initiate inflammation Activation of Antigen presentation Innate immune cells occurs in the lymph nodes PAMP = pathogen- IL-23 – instructive associated molecular cytokine (secreted by RCSI LEADING patterns APCs) that cause T PRR = pattern recognition receptors cell differentiation  TLR = toll-like receptors Th17 subset  Th17 are important against extracellular bacterial infections T H E W O R L D T O B E T T E R H E A LT H IL-23 IL-17 Th17 IL-22 Extracellular bacterial/yeast Key Functions: infections Recruits neutrophils RCSI LEADING Release of antimicrobial peptides Increased barrier integrity  TH17 cells – good and bad! Streptococcus pyogenes Streptococcus pneumoniae Staphylococcus aureus T H E W O R L D T O B E T T E R H E A LT H Candida Secukinumab Ustekinumab Y Y IL-23 IL-17 RCSI LEADING Th17 IL-22  B CELL RESPONSE TO STREPTOCOCCI Protein antigens (e.g. Non-protein toxins) antigens (e.g. lipoteichoic acid) T H E W O R L D T O B E T T E R H E A LT H Isotype switching  production of IgG Minimal isotype switching  mainly IgM and IgA (important for mucosal production (complement activation) protection) Generation of low affinity, short-lived Generation of long-lived plasma cells plasma cells (IgM isotype) which reside RCSI LEADING which reside in bone marrow and gut in the spleen and mucosa (important Production of memory B cells which point for hyposplenism) reside in marginal zones of secondary No memory cells lymph organs ANTIBODY RESPONSES IgG, IgA IgG T H E W O R L D T O B E T T E R H E A LT H IgG, IgM Antibodies will neutralise, activate complement, promote opsonisation Neutralising antibodies are directed towards the Streptococcus to RCSI LEADING prevent its entrance but also towards the exotoxins (e.g. Streptolysin O & S) Opsonisation ‘tags’ the Streptococcus for recognition and phagocytosis  1. Antigen recognition – Which FOLLOW THE STREPTOCOCCUS! TLR is responsible for the recognition of the surface of the Streptococcus? A. TLR2 1 B. TLR7 Menti meter code: C. TLR9 T H E W O R L D T O B E T T E R H E A LT H 2. Signalling – What are the main cytokines produced by macrophages? Menti meter A. IL-4 and IL-5 code: 2 B. IL-22 and IL-17 C. TNF and IL-1 3. Adaptive immune response – What is the role of antibodies against Strep? Menti meter RCSI LEADING A. Opsonisation code: 3 B. Neutralisation C. Complement activation D. All of the above  HYPOSPLENISM = REDUCTION OR LOSS OF SPLENIC FUNCTION The clearing of extracellular bacterial infections requires antibodies, which are produced by B cells Spleen is a crucial secondary lymphoid organ where: T H E W O R L D T O B E T T E R H E A LT H  B cells finish their development  T and B cells await for antigens circulating in the blood  The short-lived plasma cells for IgM antibody production Causes of hyposplenism: are stored Congenital absence of spleen (asplenia) Surgical removal of the spleen (trauma, autoimmune cytopenia, Lymphoproliferative disorder) Functional hyposplenism (Coeliac disease, Sickle- RCSI LEADING cell anaemia) Reduced splenic function no short lived plasma cells for IgM production recurrent bacterial  MANAGEMENT OF HYPOSPLENISM Management is aimed at reducing infection Prophylactic antibiotics starting at birth (in case of asplenia) or after surgical splenectomy (life long) Immunisation with vaccines 2 weeks prior to surgery T H E W O R L D T O B E T T E R H E A LT H or as early as possible – Polyvalent pneumoccal – Haemophilius Influenzae b – Meningitis C – Annual influenza Annual measurement of antibody titers is recommended Patient education – i.e. make sure they know they are RCSI LEADING at risk! They should be advised about risk of travel and insect bites + carry a splenectomy card or wear a medic-Alert bracelet  IMMUNE RESPONSE TO OTHER EXTRACELLULAR PATHOGENS T H E W O R L D T O B E T T E R H E A LT H eg. Helminth infections Schistosoma mansoni, Ascaris lumbricoides, Trichuris trichiura, Necator americanus, and Ancylostoma duodenale RCSI LEADING  RECOGNITION AND ACTIVATION OF INNATE IMMUNITY Release of ‘secretory antigens’ IL-1/TNF/IL-8 – initiate inflammation T H E W O R L D T O B E T T E R H E A LT H Antigen presentation occurs in the lymph Activation of nodes Innate immune cells IL-4 – instructive cytokine that cause T PAMP = pathogen- cell differentiation  associated molecular RCSI LEADING patterns Th2 subset PRR = pattern recognition receptors TLR = toll-like receptors  Th2 are important against helminths infections T H E W O R L D T O B E T T E R H E A LT H Helminth IL-4 IL-4 Th2 IL-5 IL-13 Key Functions: Isotype switching towards IgE RCSI LEADING & IgG Recruits mast cells and eosinophils  IgE & Eosinophil/mast cell – mediated reactions Mast cell granules contain proteases and other substances that directly kill the worm T H E W O R L D T O B E T T E R H E A LT H They also secrete histamine  increase secretion of mucus in the gut and help ‘peristalsis’ (i.e. mast cells help getting rid of the killed worm!) Eosinophil granules contain proteins that are toxic for the parasite RCSI LEADING The presence of IgE antibodies help in case of a secondary infection!  TH2 associated diseases Increased susceptibility to Asthma and allergy: T H E W O R L D T O B E T T E R H E A LT H High levels IgE High levels mast cell activity IL 4 IL 5 Th 2 IL4 RCSI LEADING