Module 2

mucosal infections

• skin and various mucosae lining organs are in continuous contact with environmental microbes

• aberrant immune responses to harmless agents — celiac disease

  • most pathogens that cause death are either mucoasal surface pathogen or enter through mucosal surface

prevention of infection in the gut

• presence of thick mucus layer keeps most organisms in lumen away from intestinal epithelium

• antimicrobial peptides produced by intestinal epithelial cells

• IgA antibodies (produced via plasma cells in lamina propira) → transported into the lumen and neutralizes pathogens before entry into epithelium

distinctive features of mucosal immune system

• intimate interactions between mucosal polarized epithelia and lymphoid tissues

• discrete compartmants of diffuse lymphoid tissue and organized stuctures — peyer’s patch, isolated lymphoid follicales and tonsils

• specialized antigen uptake mechanisms

• broad surface area in contact with environmental agents/microbes

epithelium types

• simple columnar

• pseudostratified columnar epithelium

• non keratinized stratified squamous epithelium

• keratinized stratified squamous epithelium

effector mechanisms of the mucosal immune system

• activated/memory T cells predominate even in the absense of infection

• multiple activated ‘natural’ effector/regulatory T cells present

• production of mucins and mucus

• secretory IgA antibodies

• production of antimicrobial peptides (AMPs)

• presense of distinctive microbiota

Discrete compartments of the mucosal immune system

• cells of mucosal IS located both in anatomically defined compartments + scattered through mucosal tissue

• lymphocytes are in organised tissue (peyer’s patch), isolated lymphoid follicles forming GALT

• mesenteric lymph nodes (gut draining LN) — connected to peyer’s patch and intestinal mucosa via afferent lymphatic vessels (largest LN in body)

immunoregulatory environment of MIS

• active down regulation of immune response predominates at homeostasis (to food and other innocuous antigens)

• inhibitory macrophages and tolerance-inducing dendritic cells

• high number of FoxP3+ Treg cells and FoxP3-Tr1 cells

goblet cells

• simple columar epithelial cells that develop from stems cells in bass of crypt

• contain mucopolysaccharide in secretory granules — expand up to 500-fold after release

• act as a physical barrier to the motility and feeding of bacteria and other pathogens (intestinal parasites)

• releases Th2 cytokines including IL-5 and IL-13

gastrointestinal cells and host defence

intestinal epithelial cells produce antimicrobial peptides that kill pathogens or reduce their entry into the epithelium

Microfold (M) cells

transport antigens from the lumen of the intestine to underlying dendritic cells for antigen delivery

Paneth cells

• in the small intestine

• produce antimicrobial peptides such as cathelicidins and defensins

tuft cells

detect pathogen molecules (chemoreceptions), and produce IL-25, which induced ILC2s to produce IL-4 and IL-13 and help initiate a Th2 type response

M cell structure

• thin glycocalyx, short microvilli and large fenestrations in htier membranes

• able to transport antigens in endocytic vesicles across the cytosol and deliver them via endocytic vesicles across the cytosol → deliver them by exocytosis at the basolateral membran

• convoluted basal membranes in M cels form “pockets” → allows close contact with DC for antigen presentation

mucosal macrophages

• lamina propria contains largest population of macrophages in the body → highest population in small intestine

• located immediately under the epithelium, rep 75% of all mononuclear phagocytes

• highly phagocytic but with a non-inflammatory profile

major function of gastrointestinal tract humoral immunity

neutralise luminal microbes and mediated mainly by IgA produced in the lamina propria and transported across the mucosal epithelium into the lumen

MIS antibody production

• IgA is produced in higher amounts than any other antibody isotype, smaller quantaties of IgG and M are also secreted into the gut lumen

• IgA-secreting plasma cells are widely dispersed in the lamina propria of the gastrointestinal tract not just in lymphoid follicles

intrepithelial lymphocytes

long-lived resident effector cells that are interspersed between epithelial cells

instestinal conventional and unconventional T cells

• IEL

• most T cells are CD8+ in small intestine

• Mostly CD4+ in Lamina propria

• most T cells in healthy lamina propria have been activated by DC and express markers of effector or memory T cells

• other unconventional T cells reside in intestinal epithelium — TCRγδ and TCRαβ

IEL function

• recognise and destroy intestinal epithelial cells that display properties of infection, damage or stress

• highly motile within the intestinal epithelium and present a fully mature effector status

microbiome

• community of microorganisms that naturally that exists in a particulr environment

• bacteriome — major component of human microbiota

• virome — primarily composed of bacteriophages

• archaeome — methanogens i.e Methanobrevibacter smithii

• mycobiome — Saccaromyces, Malassezia and Candida genera

• parasitome — Blastocystic spp.

gut microbiota

• one of the largest components of our body

• composed of mostly of bacteria, also arachaea, viruses, fungi and protozoa

• symbiotic relationship with human body — protect and support the structure of intestinal mucosa

• may be influenced by a complex combination of environmental, genetic and lifestyle factors

dysbiosis

observed in metabolic disorders i.e diabetes, obesity, in cancer, autoimmune disorders, and stress related neuropsychiatric disorders i.e depression and anxiety

probiotic organisms

non-pathogenic, living microbes that provide a benefit to the host

probiotics

specific nutrients (usually complex carbohydrates) that support and encourage the growth of beneficial commensal microbes

postbiotics

referes to the waster left behind after digestion of prebiotics and probiotics and may include nutrients ie vitamins B and K, amino acids, and antimicrobial peptides

immune privilege

• coined by Peter Medawar in 1948 to describe the absence of an immune response to allografts placed into the anterior chamer of the eye or brain

immune privilege sites

• brain, eye, testes, placenta, and foetus

• have mechanisms that suppress inflammation and promote immune tolerance

• lack of classical lymphatic drainage system for antigen-presenting cells that reside in the parenchyma and perivascular spaces

• lack of cell-mediated response to instilled antigens

• prolonged survival of tissues when grafted into the brain, eyes, testicles, compared to other sites

parenchymal microglial cell

• brain resident macrophages

• enters brain very early in embryogenic phase — derived from yolk-sac precursores

• functions as immune sentinels and contributes for maintenance of brain homeostasis — synaptic remodeling, neurogenesis, and the routine clearance of debris and dead cell

choroid plexus

• modified ependymal cells that produce CSF

• acts as diffusion barrier between blood and csf and it is home to various immune cells

• choroid plexus is key point of entry for peripheral immune cells into csf space

epiplexus cells

• innate immune cells located in the choroid plexus of brain ventricles

• express markers of macrophaes, dendritic cells and microglia

• function includes phagocytosis, antigen presentation, iron accumulation and NO production

meningeal, perivascular, and ventricular macrophages

• re-stimulation of lymphocytes with peptide-MHC complexes

• allow primed lymphocytes to enter the CNS parenchyma

• derived from blood-borne monocytes (population homeostasis)

• neutrophiles and other granulocytes are absent from the health CNS

Cerebrospinal fluid

• CSF surrounds the brain and spinal cord, both internally and externally

• mainly produced by the choroid plexuses — highly vascularised tissues located within each ventricle of the brain

• reabsorption into blood via arachnoid villi

immune cell content of CSF

• 90% T cells

• 5% B cells

• 5% monocytes

• <1% dendritic cell

• T cells constitutively monitor the CNS by trafficking through CSF

CSF cytology

• Colourless and clear

• antibodies and complement is normally absent

• up 5 WBCs per mm³ in adults and 20 WBCs per mm³ in newborns

blood brain barrier

• depends on stringent ionic homeostasis

• strictly controls the movement of solutes across the CNS vasculature

• direct membrane-membrane contact between endothelial cells — tight and adherens junctions seal capillary endothelium

• pericytes aid in regulation of transcellular barrier and maintenance of vessel function

glia limitans perivascularis

inner most layer of BBB formed by astroglial endfeet surrounding blood vessels

BBB disruption

• vasogenic agents — histamie, thrombin, proinflammatory cytokines

• infectious agents — bacteria, bacterial toxins, viruses, parasites, and fungal pathogens

T cell cross reactivity

reaction of T cells to more than one distinct peptide - MHC ligand

molecular mimicry

resemblance between epitopes contained in microbial and host proteins, leading to cross-reacitivity of T cells in the host

TCR binding degeneracy

refer to the promiscuity of T cell receptor engagement that allows a single TCR to bind to different peptide-MHC complexes

original antigenic sin

• A footprint of immne response is established during the first exposure to a pathogen.

• specific memory T populations are preferentially re-expanded when reexposed to the same antigen or one that is similar

• limits the clonal expansion of new antigen specific T cells

trained immunityq

long term functional reprogramming of innate immune cells by exogenous or endogenous activation events → altered response to a secondary challenge after the return to a non-activated state

immune surveillance

physiologic function of the immune system is to recognize and destroy clones of transformed cells before they grow into tumours and to kill tumours after they are formed

tumour specific antigens

antigens that are expressed on tumours cells but not on normal cells

• some are unique to individual tumours, whereas others are shared among tumours of the same

tumour associated antigens

tumour antigens that are also expressed on normal cells.

• these antigens are normal cellular constituents whose expression is aberrant or dysregulated in tumours

Products of mutated genes

• oncegenes and mutated tumour suppressor genes produce proteins that differ from normal cellular proteins → can induce immune responses

• tumour antigens may be produced by randomly mutated genes whose products are not related to the malignant phenotype

antigens of oncegenic viruses

products of oncogenic viruses function as tumour antigens and elicit specific T cell responses that may serve to eradicate the tumours

Antigens of oncogenic viruses

• viral peptides are foreign antigens — virus induced tumours are among the most immunogenic tumours known

• virus encoded tumour antigens are not unique for each tumour but are shared by all tumours induced by same type of virus

oncofetal antigens

proteins that are expressed at a high level in cancer cells and in normal developing foetal but not adult tissues

• encoding genes are silenced during development — de-repressed with malignant transformation

tissue-specific differentiation antigens

tumours may express molecules that are normally expressed only on the cells of origina of the tumours and not on cells from other tissues

principal mechanism of adaptive immune protection against tumours

• Killing of t