Overview of Immunology

• The immune system can be categorized into the innate and specific immune systems.

• The innate immune system consists of the components that are already at the location of the infection.

  • These components respond immediately with a generalized response

• The specific immune system involves specialized T and B cells that are waiting in places away from the site of infection

  • These cells, when they’re activated, launch a specialized system that fights the specific invading pathogen

  • This system takes a little while longer to recognize the infection particularly when a pathogen is invading the body for the first time

• The complement system works alongside the innate and specific immune systems to help them destroy pathogens

Explanation of the Events During a Pathogen Invasion

- What happens when a pathogen (bacteria) invades the body?

Types of Barriers

1. There are physical barriers that need to be broken before an infection can take place (e.g. skin)

   • Most invaders will get stuck at this barrier; occasionally an invading pathogen will get through such as when there’s a cut in the skin.

   • Other physical barriers include the mucosa of the respiratory system, the gastrointestinal tract, and the urinary tract.

2. There are also chemical barriers that help destroy harmful pathogens before they can cause any infection.

   • Some examples include hydrochloric acid (HCl) in the stomach, lysozyme in sweat and tears, and lactic acid in the vagina.

Initial Immune Response

- Once an invading pathogen has broken through the physical and chemical barriers to infection, three things happen:

1. Macrophages recognize the pathogen and activate the innate immune system.

2. Dendritic cells pick up antigens from pathogens, head to the blood and lymphatic systems, and track down and activate the relevant T and B cells of the specific immune system.

3. The invading pathogen activates the complement system directly via the lectin and alternative pathways.

Innate Immune System Response to Infection

• Macrophages recognize pathogens by specific characteristics that occur only on pathogens, not on cells of the body.

  • These characteristics are known as pathogen-associated molecular patterns (PAMPs)

  • Macrophages use various receptors including toll-like receptors to recognize PAMPS.

Phagocytosis

• The process that macrophages and other phagocytes (e.g. neutrophils) use to destroy pathogens

  • After recognizing the pathogen, they wrap their cell membrane around that pathogen and absorb it within their cell.

  • The pathogen is left inside a phagosome which fuses with surrounding lysosomes that have digestive enzymes.

  • This compound breaks down the pathogen, destroys it, and processes all of the components into harmless waste products.

Occurrence of Inflammation

• If the invading pathogens are weak enough for the macrophages to deal with them alone, then it’s good, no issues.

• If the attacking army is very strong, the macrophages release cytokines (signaling proteins) to call for help, leading to inflammation.

  • Cytokines: local hormones that sound the alarm of an infection in the local area

  • An important function of the cytokines is recruiting and activating more cells of the immune system (e.g. macrophages, monocytes, and neutrophils)

  • Monocytes: precursors to macrophages that float around in the blood; differentiate into macrophages once they enter tissues and then carry out all processes done by macrophages

  • Neutrophils: phagocytes that circulate in the blood, can enter the tissues, and help destroy invading pathogens

• The inflammatory response involves various other processes that help contain and fight the infection.

  • Processes include vasodilation, increased vascular permeability, mast cell activation & degranulation (release more cytokines —> further stimulate inflammatory response), and the activation of clotting and kinin system.

Acute Phase Response

• During this response, inflammation stimulates macrophages and neutrophils to secrete more cytokines, especially the chemical interleukins (IL).

  • This leads to a more systemic inflammatory response.

• Cytokines, specifically interleukin 1, are sent to the brain, signaling it to produce a fever.

  • This leads to high temperatures that are poorly tolerated by pathogens, causing reduced appetite and lethargy.

  • The person can then conserve more energy that can be used to fight the infection.

• Interleukin 6 is sent to the liver to produce acute-phase proteins that act according to opsonins.

• Interleukin 8 is released to recruits and activates more neutrophils

• Interleukin 2 and 12 activate natural killer cells

• The release of tumor necrosis factor-alpha does all of these effects by itself

Importance of Opsonins

• These are complex molecules that attach themselves to pathogens and help macrophages & neutrophils with recognition and phagocytosing the pathogen

  • Ex. C Reactive Protein (CRP): produced by the liver in response to IL-6; the level of CRP is measured to assess the amount of inflammation and severity of the infection

**Summary of Innate Immune System: a generalized system that recognizes and responds to invading pathogens by causing an inflammatory response and recruiting cells that destroy pathogens via phagocytosis

Complement System

• A series of complement proteins, labeled C1 - C9, are involved in this process of destroying pathogens.

• Complement Cascade: occurs once a complement system is triggered and the proteins start to activate each other

  • Various products of this cascade have crucial functions such as acting as opsonins, triggering further inflammation, and directly destroying the pathogen.

Triggers of the Complement System

1. The Lectin Pathway - activated directly by pathogens

2. The Alternative Pathway - activated directly by pathogens

3. The Classical Pathway - activated by antibody-antigen complexes that arise from the specific immune system

Specific Immune System

• The two crucial components of this system are the T and the B cells which are both types of lymphocytes.

  • These cells can freely float around the lymphatic system and the blood, but most of their time is spent in the lymph nodes and the mucosa-associated lymphoid tissue.

• Each pathogen has molecules that are unique to them (antigens)

  • Each T cell has T cell receptors that are specific to a single type of antigen

  • B cells have antibodies on their cell membrane that are also specific to a single type of antigen

  • Resulting in millions of different T and B cells that are all specific to a single type of antigen

Role of Dendritic Cells

• When a new pathogen arrives and causes an infection, the T and B cells that are specific to that pathogen need to be alerted.

  • The problem is that certain lymphatic tissue (e.g. lymph nodes) are in a different location than the infection site.

  • Dendritic Cells: messengers that pick up the antigens at the site of the invasion, display them on their cell surface, and bring them to the lymphatic tissue through the blood and lymphatic system.

  • Upon their arrival, all the T and B cells look at the antigen to see if they recognize it.

  • The T and B cells that are found to be specific to the antigens are then activated.

Specific Immune Response

• Starts with the dendritic cell presenting the antigens on their HLA class 2 molecules to the CD4 cells (type of T cells)

• The CD4 cells multiply and become T helper cells which present antigens on their HLA class 1 molecule that can be recognized by CD8 cells.

Functions of T Helper Cells

• T helper cells secret cytokines that are responsible for making the CD8 cells multiply and differentiate into cytotoxic T cells

• T helper cells release cytokines that stimulate B cells to multiply and differentiate into:

  • Plasma Cells: release large amounts of antibodies

  • Memory B Cells: part of the immune memory that responds quickly to future infections of that specific pathogens

• T helper cells also travel to areas of infection and secrete cytokines that help to recruit monocytes and macrophages to the infected tissue

  • The macrophages are activated to cause inflammation and start phagocytosis

Importance of Cytotoxic T-cells

• Cytotoxic T-cells are responsible for killing cells that have been infected by pathogens (e.g. virally infected cells)

  • They need to be attached via the T-cell receptor and the HLA class 1 molecule, containing the relevant antigen protein, on the infected cell

  • After the attachment, there are two killing mechanisms to choose from:

    • Granule Exocytosis: the infected cell is sprayed with enzymes that destroy the membrane, leading to cell lysis and cell death

    • Activation of the FAS Molecule: a “self-destruct switch” that causes the cell to undergo apoptosis

Roles of Plasma Cells and Antibodies

• Plasma Cells: B cells that have differentiated and become antibody-producing cells with the job of producing tons of antibodies that are specific to the invading pathogen

• Antibodies: proteins that are Y-shaped with a variable region that varies in shape to match different antigens and a fixed region that can be recognized by many cells of the immune system

  • These proteins float around the blood and attach themselves to antigens that match their specific variable region

• These antibodies help the immune system fight pathogens in multiple ways:

  • Attaching themselves to enemy toxins or antigens and neutralizing their toxic effects

  • Attaching themselves to receptors of viruses and bacteria, preventing them from carrying out their function (e.g. stopping viruses from identifying cells that they want to invade)

  • Agglutination: attaching themselves to pathogens and then clumping together to slow the spread of that pathogen down

  • Attaching themselves to pathogens while acting as opsonins that are highly specific invading pathogens to help macrophages and neutrophils recognize and destroy the pathogen