Introduction to Immune System

Question 1

What is Immunology?

Answer 1

Study of our body’s systems for preventing and treating diseases.

Question 2

How is the immune system organised?

Answer 2

The Immune System is split into a frontline defence (Innate Immunity) and a second, more specific defence (Adaptive Immunity).
The adaptive immunity can be humoural (ie. B cells and antibodies) or it can be cellular (ie. T cells).

White Blood Cells (WBCs) are key players in the immune system.

Question 3

Briefly, describe the innate immune system.

Answer 3

Innate immune system is your ever-present defence against infection. It is made up of barriers that keep viruses, bacteria, parasites and other foreign particles out of your body or limit their ability to spread and move throughout the body.
The importance of innate immunity is demonstrated by the fact that you are normally healthy despite the barrage of potential infectious challenges that you face every minute.

Question 4

What does the innate immune system include?

Answer 4

• EPITHELIAL BARRIERS to the environment (eg. skin, gastrointestinal tract, respiratory tract) that prevent microbe entry
• SECRETIONS at mucosal surfaces - flushing action and antimicrobial properties
• CELLS that are resident in tissues (eg. mast cells) or circulating in the body (eg. neutrophils)
• Circulating PROTEINS in the blood (eg. complement proteins)
• CYTOKINES (eg. interferons) that are locally produced by infected cells
• Dendritic cells, granulocytes and macrophages are also present

Question 5

What are the main functions of innate immunity?

Answer 5

• prevention, control and elimination of infection
• removal of damaged cells and initiation of tissue repair
• activate the adaptive immune response
• influence the type of adaptive response that will develop
• We would not be able to survive on our adaptive immune system alone.
  The adaptive immune system takes a few days to activate and reach maximal responses, while the innate immune system provides immediate and early protection.

IMPORTANT FEATURES
- it’s the first line of defence in preventing infection
- it responds to microbes and products of injured cells
- it has non-specific activity
- it has no “memory”, so if the challenge is repeated, the innate immune response will be the same

Question 6

What is phagocytosis and why is it important?

Answer 6

Phagocytosis is a process by which cells internalise solid matter, including microbial pathogens.
This is a vital part of the innate immune response to pathogens, and plays an essential role in initiating the adaptive immune system.

Most cells are capable of phagocytosis, but it is the professional phagocytes of the immune system that truly excel at this process. These cells include NEUTROPHILS in circulation, MACROPHAGES in tissues and DENDRITIC CELLS.
In these cells, phagocytosis is a mechanism by which microorganisms can be contained, killed and processed for antigen presentation.

Question 7

How do immune cells know when to get to work?

Answer 7

The immune system detects ‘danger’ through a series of pathogen-associated molecular patterns (PAMPs) or damage-associated molecular pattern molecules (DAMPs) working in concert with both positive and negative signals derived from other tissues.

PAMPs
- Small molecular motifs conserved within a class of microbes. A vast array include glycans, lipopolysaccharides, bacterial flagellin, lipoteichoic acid, peptidoglycan and nucleic acid variants normally associated with viruses, such as double-stranded RNA

DAMPs
- Molecules released by stressed cells undergoing necrosis. Some are proteins - heat-shock proteins and cytokines. Non-protein DAMPs include ATP, heparin sulfate, and DNA

Both are recognised by Pattern Recognition Receptors (PRRs) on immune cells. Once recognition occurs, PRRs trigger proinflammatory and antimicrobial responses by inducing the release of a broad range of cytokines

Question 8

Describe dendritic cells.

Answer 8

Dendritic cells are widely distributed in lymphoid tissues, mucosal epithelium and body organs. They are important in phagocytosis (as they are phagocytes).
This is because their main function is to process antigen material and present it on the cell surface to the T cells of the immune system. They act as messengers between the innate and the adaptive immune systems.

Question 9

Briefly, describe the adaptive immune system.

Answer 9

The adaptive immune system is the second line of defence and responds to infection. It takes day-weeks to develop the full immune response required for complete removal of infection, but it is also:
- potent
- responsive to any potential foreign entry
- highly specific
- has ‘memory’

The importance of adaptive immunity is that it provides a powerful defence against infection if the innate immune system is breached.

Question 10

What are the main (cellular) components of the adaptive immune system?

Answer 10

• DENDRITIC CELLS: they capture, process and present antigens
• T-LYMPHOCYTES: they control the immune response by providing ‘help’ to B cells and macrophages (helper T cells), and directly kill off infected or tumour cells (cytotoxic T cells)
• CYTOKINES: they’re soluble proteins secreted mainly by T cells that control activities of other cells
• B LYMPHOCYTES: they produce and secrete antibodies, which are proteins that specifically bind target molecules (antigens) on microbes or cells

Question 11

What is the Lymphoid System?

Answer 11

Immunological cells are largely organised (not randomly) into tissues and organs for best efficiency. This is an advantage as it protects key areas of the body.
Collectively, these structures are known as the lymphoid system.

Question 12

Define primary and secondary lymphoid organs.

Answer 12

PRIMARY LYMPHOID ORGANS are sites of maturation of white blood cells. The WBCs differentiate from stem cells, multiply, are programmed and mature into functional cells.
SECONDARY LYMPHOID ORGANS provide the site of interaction between antigens and WBCs. They also allow the spread of the immune response. Secondary lymphoid organs are associated with systemic and mucosal immune compartments.

Question 13

Describe the Lymphatic System.

Answer 13

The lymphatic system is part of the circulatory system and an important part of the immune system. It comprises a network of lymphatic vessels that carry lymph fluid and cells from the tissues back into the bloodstream. The lymphatic system acts as a countercurrent system, draining from the tissues all the waste materials and recycling surplus fluid, salts, proteins, fat and immune cell back into the body.
- Is an ‘open’ system

The lymphatic system requires the contraction of the muscle around to move the fluid through it. The fluid moving along is much like the movement of peristalsis.

Lymph is interstitial (tissue) fluid containing salts, proteins and cells, originally formed from a plasma ultrafiltrate.

Question 14

Describe lymph nodes.

Answer 14

At regular intervals along the lymph vessels are organized structures called lymph nodes. Major areas with a lot of lymph nodes are the neck, armpits and groin.
The lymph arrives at the node by an afferent lymphatic vessel, filters through multiple layers of antigen-presenting cells, T cells and B cells, then finally exits via the efferent lymphatic vessel.

The dense concentration of immune cells provides an ideal environment for initiating immune responses and communication between immune cells. Lymph nodes are common battleground sites for the immune system and infections.

Lymph nodes are filter stations positioned at intervals along the lymph drainage route. They perform two basic functions:
- to filter and clean the lymph before it re-enters the bloodstream by sieving it out, trapping and destroying (inorganic) foreign bodies
- monitoring the lymph for telltale signs of (organic) predators, eg. infection, so playing a vital role in immune system responses

Question 15

The hallmark of adaptive immunity is the ability to specifically recognise foreign antigens. List, and describe, the two types of molecules involved in this process.

Answer 15

The two molecules involved in this process are immunoglobulins (Igs) and T cell antigen receptors (TCRs).

IMMUNOGLOBULINS: e.g IgG, IgM, IgD, IgE, IgE
Immunoglobulins (antibodies) are glycoproteins produced by plasma cells. They specifically recognise and bind strongly to particular antigens on pathogens, and prevent disease or aid in the destruction of the pathogen.
There are different classes and subclasses of immunoglobulins, which differ in their structure, biological features and distribution.
Immunoglobulins are produced by B cells, so they are a part of humoral immunity.

T CELL ANTIGEN RECEPTORS (TCRs):
T cell receptors are found on the surface of T cells. They are responsible for recognising processed fragments of antigens (peptides) which are ‘presented’ by host cells. The binding between the TCR and antigen peptides is relatively weak compared to antibodies.
When the TCR engages with the antigen peptide, the T lymphocyte is activated through a series of biochemical events (signal transduction), leading to cell proliferation and biological activity (eg. cytokine production).
TCRs are produced by T cells, so they are a part of cellular immunity.

Question 16

What are B cells?

Answer 16

B cells are lymphocytes which, when activated, become plasma cells and then produce antibodies. This is often known as humoural immunity.

The B-cell receptors bind to complementary antigens.
Mature helper T cells secrete cytokines to activate B cells. They then become plasma cells.

Question 17

Describe the structure and function of antibodies.

Answer 17

Antibodies are glycoproteins that are made by B cells and plasma cells. They bind specifically and with high affinity to ‘non-self’ antigens. Antigens are usually proteins or carbohydrates attached to, or secreted by, microbes and infected cells.
Antibodies can neutralise targets, or recruit other components of the immune system to kill targets. Once bound to a cell or bacterium, antibodies can recruit other components of the immune system to kill targets by Fc-mediated effector functions. These include white blood cells (eg. macrophages, dendritic cells). It activates the complement cascade. The antibody Fc also binds to the neonatal Fc receptor.

Question 18

Describe the structure and function of T cells.

Answer 18

T cells control the immune response and combat microbes that are inside cells (intracellular). Different T cells have different functions and are distinguished by the array of proteins on the cell surface (Cluster of Differentiation (CD) markers). Two major groups are CD4 (helper T cells ) and CD8 (cytotoxic T cells).

Depending on how the antigen is presented, different T cells are engaged, leading to different T cell responses.

T cells recognise antigens via cell-surface receptors (TCRs) proteins, that are related to antibodies. But unlike antibodies, T cells do not recognise foreign molecules in their “native” state

Immature cytotoxic T cells bind to antigens present on cell surface membrane of antigen presenting cells. Clonal expansion occurs in which mature T killer cells are formed, as well as memory T cells. Mature cytotoxic T cells kill target cells using cytokines, cytotoxic granules and the caspase cascade.

Immature T-helper cells bind to antigens present on cell surface membrane of antigen presenting cells. Clonal expansion occurs and forms mature effector cells as well as memory T cells. Mature helper T cells then secrete cytokines to “help” (activate) macrophages, B cells and other T cells.

ANTIGEN PRESENTATION
T cells only recognise antigens that have been processed within cells, and that are displayed on cell surfaces. For example, antigens derived from pathogens that have infected cells, such as viruses or intracellular bacteria, or from pathogens that have been
phagocytosed by antigen-presenting cells like macrophages and dendritic cells.

Foreign antigen fragments (peptides) are displayed at the cell surface by molecules of the major histocompatibility complex (MHC)

Question 19

How do antibodies aid immunological techniques in diagnostics and research?

Answer 19

There are two key features of antibodies: antigen specificity and high-affinity binding. These are extremely valuable in laboratory assays. They allow for rapid and highly sensitive identification of specific molecules.

EXAMPLES OF IMMUNOLOGICAL TECHNIQUES:
- ELISA
- Western blotting
- Lateral flow assay
- Fluorescence-activated cells sorting (FACS)

Question 20

What are the components of the lymphatic system?

Answer 20

LYMPHATIC CAPILLARIES:
- blind-ended
- no smooth muscle
- incontinuous basement membrane

COLLECTING VESSELS:
- smooth muscle coverage
- luminal valves (to ensure the direction of fluid occurs in one direction)
- basement membrane

LYMPH NODES

Pumping unit
- Segment of lymphatic vessels between two valves

Question 21

Describe the process of lymph drainage.

Answer 21

1) Lymph drainage begins with the absorption of fluid from the tissues.
2) Lymph is transported through larger collecting lymphatic vessels to lymph nodes
3) Lymph nodes filter the lymph where there is also interaction with the immune system.
4) After passing through a series of lymph nodes, large lymphatic vessels eventually discharge lymph into the great veins of the neck.

Question 22

What are the three main functions of the lymphatic system?

Answer 22

• fluid balance (homeostasis)
• tissue immunity
• fat homeostasis

Question 23

Describe fluid balance (homeostasis).

Answer 23

Tissue fluid homeostasis is simple: the blood vessels supply fluid and the lymph has to drain it away.

There are forces called Starling forces acting on the fluid, altering the rate at which it enters the lymphatic system. Both the Starling forces acting on the fluid and the tissue are considered.
- Amount of fluid in blood vessels determined by balance of forces in terms of hydrostatic pressure and osmotic pressure of proteins in the blood
- Bulk of the fluid from the blood system drained into lymphatic capillaries

Question 24

Describe tissue immunity.

Answer 24

The lymphatic system houses the immune system and is responsible for tissue immunosurveillance once antigen interacts with immune system (when the fluid flows through lymph nodes, it gets checked for any unwanted organisms as part of immune processing).

A common complication of impaired lymph drainage is disturbed immune cell trafficking and infections.

Question 25

Describe fat homeostasis.

Answer 25

The lymphatic system is responsible for gut fat absorption and peripheral fat reabsorption. There is a close relationship between fat and lymphatics.

Gut absorbs fat through the lymphatic system which takes it to the bloodstream for redistribution.

WHEN FAT NEEDED
Lymphatic system mobilizes it from peripheral and subcutaneous fat

WHEN LYMPHATIC SYSTEM BLOCKAGE
- Fat builds up

OBESITY
- Obesity could be caused by bad lymph drainage (one option- not always!)

Question 26

When do the following occur?

• LYMPHOEDEMA
• CHRONIC OEDEMA
• VENOUS OEDEMA
• ELEPHANTIASIS
• POST-THROMBOTIC SYNDROME
• PODICONIOSIS

Answer 26

OEDEMA - Fluid swelling of a tissue

LYMPHOEDEMA
Lymphoedema occurs when the lymphatic system fails.
A lymphoedema results in swelling, such as a leg with a build-up of fluid, cells and fat, as well as a predisposition to infections.

Lymphoedemas can occur after breast cancer treatment surgery (removing lymph nodes to restrict cancer spread but drainage route becomes overwhelmed - swelling of arms occurs) or treating heart failure(pressure in the veins entering the heart builds. The higher venous pressure backs up the lymph capillaries in the leg), for example.

CHRONIC OEDEMA
Chronic oedema occurs when there is lymphatic failure.
Either the lymph drainage is insufficient, or the lymph load (vascular fluid filtration) exceeds the lymph drainage capacity.

VENOUS OEDEMA
High lymph load from venous hypotension overwhelming lymph drainage
- if persists after treatment, suggest permanent damage to lymphatic system

ELEPHANTIASIS
- Caused by a mosquito bite-transmitted parasite that damages or blocks the lymph system in the groin
- Symptoms are swelling of legs

POST-THROMBOTIC SYNDROME
- Usually occurs after a DVT
- Occurs as the veins are so damaged, so fluid drainage becomes severely restricted

PODICONIOSIS
- When the lymph vessels become poisoned from silicates in the soil entering the skin and lymph system when children walk barefoot

Question 27

What are the three mechanisms for chronic oedema?

Answer 27

• Lymphatic failure with increased capillary filtration (high lymph load that is overwhelming lymph drainage capacity) results in RELATIVE LYMPHATIC FAILURE
• Lymphatic failure with no increased capillary filtration (normal lymph load) results in ABSOLUTE LYMPHATIC FAILURE (LYMPHOEDEMA)
• Lymphatic failure resulting from sustained increased capillary function exhausting lymph drainage capacity results in ABSOLUTE LYMPHATIC FAILURE (LYMPHOEDEMA)

Question 28

What is primary lymphoedema?

Answer 28

It is the intrinsic failure of the lymphatic system. It’s caused by alterations (mutations) in genes responsible for the development of the lymphatic system.
The phenotypes vary in age of onset, site, inheritance patterns, associated features, genetic causes, etc.

Question 29

What is the management of lymphoedema/chronic oedema?

Answer 29

Because there is not one drug or one operation that is known to improve lymph drainage, treatment has to be physically based, intended to stimulate lymph drainage and reduce blood vascular filtration (lymph load). Examples of this would be compression of the affected area, and performing exercise.

Question 30

List some diseases of lymphatic dysfunction.

Answer 30

• RESPIRATORY DISEASES: asthma, chronic airways disease
• CVS: hypertension, plasma volume homeostasis, atherosclerosis
• CNS: glaucoma, dementia
• INFECTION AND IMMUNITY: HIV, organ rejection, autoimmunity, cellulitis, sepsis, wound healing, tissue repair
• GI: Crohn’s disease
• CANCER METASTASES
• OBESITY AND HYPERCHOLESTEROLAEMIA

Question 31

What is the purpose of sentinel lymph node biopsies?

Answer 31

Detect the lymphatic spread of cancer and guide treatment

Question 32

What is inflammation?

Answer 32

Process whereby immune cells (which are normally distributed throughout the body) can be recruited and concentrated to a site of infection or damage

Following PAMP or DAMP recognition, PRRs trigger proinflammatory and antimicrobial responses by inducing the release of a broad range of cytokines from white blood cells e.g macrophages will release TNF-α and IL-1β, which causes vasodilation and increased migration of leucocytes to the site of infection.

• Increased blood supply to the affected area;
• Increased permeability of the vasculature ;
• Migration of WBCs out of the blood capillaries into the affected tissue