Response to environmental effects and structural homeostasis

For the exam

What is the immune system?

Complex network of cells, tissues, organs and substances that helps the body fight diseases.

Main functions of the immune system?

• Defend against foreign particles

• destroy

• maintain homeostasis

Benefits of the immune system?

• Protection against invaders

• elimination of altered self

Detrimental effects of the immune system?

• Discomfort due to inflammation

• Damage to self when autoimmunity occur.

Components of the immune system?

• Mucous membrane

• Tonsils

• Thymus

• Lymph nodes

• Spleen

• Bowel

• Bone marrow

• Skin

Primary lymphoid organs

Where immune cells are generated and matured:

• Thymus, bone marrow

What happens to primary lymphoid organs?

Atrophy with age and has no contact with antigen.

Secondary lymphoid organs

Organs which maintain mature naive lymphocytes and initiate adaptive immune response.

• Have contact with antigens

• Increase in size with age.

Haematopoiesis

Place where all immune cells are born. Cascade of immune response starts once needed.

1. Haematopoietic stem cells

   1. Lymphoid progenitor cells

      1. T-cells

      2. B-cells

   2. Myeloid progenitor cells

      1. Platelets

      2. Granulocytes

      3. Monocytes

      4. Erytrocytes

What is important regarding the immune system?

Balance. Activated when needed and suppressed when not needed.

How do we classify immune system?

• Innate immunity (non-specific)

• Adaptive immunity (specific)

Further classification of immune system?

• Innate;

  • Humoral: complement, interferon, TNF

  • Cellular: Cells which phagocytise

• Adaptive;

  • Humoral: antibodies

  • Cellular: T-cells, B-cells and other effector cells.

What is innate immune system?

The immune system we are born with which is antigen independent and has no time lag.

• Phagocytes

• Dendritic cells

• Complement

• Natural killer cells

What is adaptive immune system?

The immune system which develops over time.

Antigen dependent and can recognise what response is best suited for a specific antigen —> develops memory.

Takes 14 years until activated and developed.

• B-cells

  • Plasma cells

    • Antibodies

• T-cells

  • Effector T-cells

Components of innate immunity?

Physical barriers: skin, gut villi, lung cilia

Soluble factors: Protein and non-protein secretion

Cells: Phagocytes, NK cells, eosinophils

Components of adaptive immunity?

Physical immunity: none

Soluble factors: immunoglobulins

Cells: T- and B-cells

Why is innate immunity needed?

• Detects overwhelming reactions quickly.

• Protects us until adaptive immune system activates.

• Sends stimulus to adaptive system.

Physical components of innate immunity?

• Barrier between microbes in environment and host:

  • Skin + mucosal surface

• Levels of physical protection

• Secretion from epithelial cells

• Intraepithelial T-cells

What are the levels of physical protection in innate immunity?

• Tight junctions

• Keratin

• Mucus assisted by cilia

What do epithelial cells produce as defence?

Antimicrobial chemicals:

• Defensins

• Further impede entry of microbes

How do cilia and mucus protect us?

Bacteria get stuck in the mucus of the respiratory tract and cilia sweep this mucus into throat for coughing or swallowing.

How does saliva protect us?

Chemicals break down bacteria.

What happens if bacteria survive saliva?

Broken down by stomach acid

What does macrophages do in innate immunity?

Remove damaged tissue, cells and bacteria through phagocytosis.

• Antigen presentation to T-cells.

What does neutrophils do in innate immunity?

Contain granules with bactericidal enzymes and are 80% of leucocytes in humans.

What does dendritic cells do in innate immunity?

Present antigen to T cells to initiate adaptive immune system.

What do Natural killer cells do in innate immunity?

Kill virus and tumor cells without specificity. '

• Release perforin

• Release granzymes which induce apoptosis

What do mast cells do in innate immunity?

Release inflammatory mediators when damaged and under influence of IgE.

• Release histamine, heparin and cytokines

What is phagocytosis?

Attachment to microorganisms using cell surface receptors or adapter molecules.

• Pseudopods hugs microbe and fuse to form phagosome

• Lysosome fusion which braks down microorganism through enzymatic reaction.

• Release of undigested products.

What are soluble components of innate immunity?

Molecules that respond to microbes and promote innate response in blood and ECF.

1. Act as opsonins to enhance phagocytosis

2. Promote inflammation

• Complement,

• Cytokines

• chemokines

• defensins

What is the complement system?

A series of heat-labile serum proteins which when activated acts as enzyme which cleaves several molecules of the next component in the sequence.

What are the parts of the complement system?

Major fragment: With one site that binds to cell membrane and other site which enzymatically cleaves next complement compound.

Minor fragment: Generated when component is cleaved and increase vascular permeability (C3a) in inflammation. Other attract neutrophils and macrophages for subsequent opsonisation and phagocytosis (C5a).

• Enzyme site which destroys pathogen

• Cleavage site which cleaves other complement fragments

How is complement system activated?

• Antigen-antibody complex

• MBL: bound to surface carbohydrates on pathogens

• Alternative pathway

How is the complementary system regulated?

1. Some activated compounds are unstable and will decay.

2. Inhibitors: C1 esterase inhibitor, Factor I and H.

3. Proteins in cell membrane block complement action.

What are the major actions of innate immunity?

• Inflammation

• Phagocytosis

What makes lymphocytes special?

• Express highly diverse membrane receptors and recognise wide variety of foreign substances.

• Takes a week to develop but provides long-term memory which ensure faster and better response under second infection.

Categories of adaptive immunity?

• Natural:

  • Active: through contact with diseases

  • Passive: through mothers milk

• Artificial:

  • Active: Vaccine with suppressed antigen

  • Passive: immune serum with immunoglobulins.

What are the types of adaptive immunity?

• Humoral immunity:

  • Mediated by secreted antibodies

  • Defend agains extracellular microbes

• Cell-mediated immunity

  • Mediated by T-cells and their products

  • Defence against intracellular microbes

List all the phases of adaptive immune response.

1. Antigen presented to naive T-cells or sometimes B-cells.

2. Activation and multiplication of lymphocytes.

3. Differentiation

4. Antigen elimination

5. Apoptosis of cells and production of memory cells.

How does lymphopoiesis work?

Lymphoid progenitor cells differentiate into B or T cells.

• Immature B-cells mature in spleen and lymph nodes into plasma cells.

• Immature T-cells mature in thymus.

How are T-cells activated?

Antigen must be presented on the surface of host cells by antigen presenting cells and need a costimulatory signal.

What are the main antigen presenting cells?

• Dendritic cells: activate naive T-cells

• Macrophages: Activate effector T-cells

• B-cells: B-cells activate into plasma cells and antibodies are produced.

What are helper T-cells?

T-cells with receptors recognising antigens and release cytokines to stimulate B-cell division.

What does B-cells do?

• Produce antibodies

• Differentiate into plasma cells or memory cells.

  • Plasma cells produce antibodies

  • Memory cells retain memory of invader for future reference.

How are B-cells activated?

Recognise antigen without APC or MHC molecule.

antibody on cell surface act as B-cell receptor.

Secondary signals promote increased activation and signalling.

What can antibodies do?

• Neutralize microbes

• Opsonisation and phagocytosis of microbes.

• Lysis of microbes

• Activation of complement system.

What occurs when the immune system is to active?

Autoimmune diseases and allergy

What happens too weak system?

Immunodeficiency

What is homeostasis?

Self-regulating process by which biological systems maintain stability.

What defines as mucosa?

A mucous membrane that lines cavities in the body and covers surface of internal organs which contains components of the innate and adaptive immune system.

Located strategically.

Structure of the mucosa?

• Epithelium

• Loose connective tissue (lamina propria)

• Smooth muscle (muscular mucosa)

  • With certain cells which secrete mucus, digestive enzymes and hormones.

Characteristics of the mucosal immunity?

• Largest organ of immune system (300m²)

• Selectively permeable and can distinguish between nutrients and foreign particles.

• Immune reactions are concentrated on the surface of the mucosa.

• 80% immunoactive cells are located here.

What does mucosal immunity do?

• A system that occurs at mucosal membranes of intestine, urogenital tract and respiratory system

• Protects and maintains tolerance.

What is the innate defence of the mucosal immunity?

• Physical barriers:

  • epithelium,

  • goblet cell mucus production,

  • cilia.

• Mucosal antibacterial molecules:

  • a-defensins in intestine,

  • b-defensins in oral cavity,

  • lactoferrin in mammary and salivary glands.

• Cellular:

  • mucosal NK,

  • dendritic cells.

What does the mucosal immune system consist of?

• Cellular

• Humoral

• Defence mechanisms

• Physical barriers

• Chemical factors as antimicrobial peptides and pH.

What are the physical barriers in mucosal immunity?

Tight junctions

Rapid turnover of epithelium from stem cells.

Presence of mucus

Ciliated surface

Optimal pH

Presence of microflora.

What are defensins?

Antibacterial beta-sheet proteins with antimicrobial effects similar to antibiotics.

Cellular part of mucosal immunity

• NK cells are found in lamina propria and intraepithelial compartment.

• Secondary lymphoid tissue

  • In upper respiratory tract and gastrointestinal tract

  • effector tissues.

  • Inductive site

What is effector tissue?

The vast areas of the mucosal immune system charcterized by diffuse collections of lymphoid cells and termed the effector tissues. These include the interstitial tissues of the mammary, lacrimal, salivary, sweat glands, lamina propria of the GI tract.

What is the inductive site?

Organized lymphoid tissue (MALT)- discrete collections of lymphoid tissues that share distinctive features, including a unique type of epithelium, unique set of cells- antigen presenting cells, B cells (with predominant production of IgA).

What is the aim of MALT?

To protect permeable surface from microbes by initiating immune mechanisms in organised follicles.

• Is highly specialised

• MALT describes all organised systems of the lymphoid tissue.

Why is sIgA a big molecule

• Easier to survive gut environment and it survives by being bound to a receptor.

Main functions of microbiota?

• Metabolism

• Tolerance

• Regulate immune response

• Protects

How does the mechanism of MALT work?

• M-cells take up microbes and present it to;

• Antigen presenting cells (phagocytes) which further presents the antigen to:

• T-helper cells which presents it to

• B-cells which produce antibodies.

What are the functions of the mucosal immune system?

• First line defence from harmful substances and microbes;

• Prevents systemic immune responses to commensal bacteria and food antigens;

• Regulates appropriate immune responses to pathogens.

What is and how does GALT work? (peyer´s patch)

It is an organised lymphoid follicle in the gut.

• Antigen enters through M-cells

• Present it to antigen presenting cells which introduce the antigen to CD4+ (T-helper cells)

• They activate B-cells to form plasma cells which secrete secretory IgA

What happens with antigens that enters by mistake, (not entering (Payer´s patch).

CD8+ suppressor cytotoxic cells catch the antigen and activate cytotoxic T-cells to destroy the pathogen.

What is sIgA?

Immunoglobulins secreted in the mucosa by B-cells bound by J-chain in a dimer.

What is the action of sIgA?

• Destroy pathogen through cytotoxic activity

• Connect to antigen in lamina propria and remove through transcytosis.

• Bind to proteins inside epithelial cells and take them out through transcytosis

What is transcytosis?

sIgA enters epithelial cell through endocytosis and transports the antigen to the surface where it is expelled from the endoscope into the lumen again.

Roles of immunoglobulin A?

• Protects by inhibiting microbial adherence, neutralising virus and toxins.

• Anti-inflammatory

• The structure prevents IgA from getting broken down.

• Opsonisation

What is opsonisation?

Opsonization is an immune process which uses opsonins to tag/mark a foreign pathogen for elimination by phagocytes.

Functions of the microbiota?

• Metabolise

• Fill niches to prevent pathogen colonisation.

• Develop immune system

• Maintain tolerance

E-coli is part of our microbiota. Still we can get sick with e-coli, why?

Because tolerance is disrupted and E-coli most likely starts to overpopulate and could even fill niches which they normally do not do. For instance travel to blood stream.

Why does microbiota differ in different places of the body?

Because different sites have different environments with different needs.

Influencing factors of the microbiota?

• Age

• Birth

• Drugs

• Disease

• Exercise

• Diet

• Antibiotics

How does antibiotic affect our natural microbiota?

It not only kills of the bad bacteria but also kills our good and non-harmful bacteria which leads to dysbiosis which can develop into other diseases.

How can we modulate our microbiota?

• Probiotics

• Prebiotics

• Postbiotics

• Microbiota transplantation

What cells are involved in the innate immune response?

• Macrophages

• Granulocytes

• Mast cells

• Dendritic cells

• Complement protein

• NK

How effective is the innate immunity?

Does not require prior activation to be effective and activates immediately when meeting antigen.

Lysosome

Secreted by macrophages which catalytically cleaves gram-negative bacteria.

Lactoferrin

A multifunctional protein found in secretory fluids (milk, saliva, tears) that interacts with DNA and RNA acting bactericidal and fungicidally.

Interferrons

Proteins produced by many cells (macrophages and DC) in response to viral infection, inhibiting viral replication.

Antimicrobial peptides

Secreted by neutrophils, intestinal wall, pancreas and kidney epithelial cells which damages microbial membranes. Causes intracellular processes by suppressing synthesis of DNA or proteins.

Tumor necrosis factor (TNF)

Secreted by macrophages and dendritic cells.

• Activate endothelial cells triggering inflammation and coagulation. Increased blood flow and immune cell recruitment.

• Activate neutrophils to migrate.

• In the liver triggers acute phase protein synthesis.

• Triggers fever from the hypothalamus and catabolises fat (cachexia).

• Triggers apoptosis of cells.

Cytokines

Low molecular weight proteins or glycolipids important in cell signalling that are secreted by cells after stimulation.

Type I interferons (IFN-a, IFN-B)

Produced from macrophages and fibroblasts

• Activate NK cells

• Induce expression of MHC-I

Interleukin 1 (IL-1)

Produced by macrophages and endothelial cells

• Activates endothelial cells and neutrophils

• Induce fever and synthesis of acute proteins

IL-6

Produced by macrophages, endothelial and T-cells

• Induces synthesis of acute phase proteins

• Induce proliferation of B-cells and antibodies

IL-10

Produced by macrophages and T helper2 cells

• Induce proliferation of B-cells

• Inhibits pro inflammatory cytokine products

IL-12

Macrophages and dendritic cells produce them

• Activates NK and T-cells

• Induces synthesis of IFN-gamma

• Increases cytolytic activity

• Induces differentiation of T-cells toward Th1 cells

Why are receptors important?

They recognise surface compounds common to many bacteria and can phagocytise them. When phagocytized in macrophages, synthesis of biologically active substances causes inflammation.

Neutrophils

First to appear during inflammation

• Protects against bacterial invasion

• Secrete biologically active substances

Eosinophils

Have same enzymes as neutrophils except antibacterial.

• Detox of poisons

• Phagocytizes immune complex

Basophils

Allergic reactions: degranulates and produces heparin and histamine.

How does macrophages activate?

Monocytes circulate in the blood and migrate into the tissue where they become macrophages.

Activated by T-cells cytokines —>

• size increases,

• lysosomal enzymes increase,

• metabolism activates.

How can tissue repair be bad?

It can lead to fibrosis where an overproduction of collagen decreases elasticity and function of the tissue. For instance, in lungs during cystic fibrosis.

What does NK cell do?

Lyse virus infected cells and produce interferons.

Mast cells

Degranulates due to trauma, heat, UV and releases histamine and heparin.

Dendritic cells

Antigen presenting cells and stimulating signals.