Genetics of the Immune system Immune system - protects us against foreign material proteins,...

Genetics of the Immune system Immune system - protects us against foreign material

proteins, viruses, bacterial infections 

Immune system has two major divisions.

Non-Specific Response- block entry of foreign agents into the body- block the spread of foreign agents if they

get into the body Specific Responses

- antibody-mediated immunity - humoral response

- cell-mediated immunity – cellular response

Foreign versus Self

To protect the body from harmful organisms, the immune system identifies foreign molecules as “nonself” and destroys those cells.

Molecules recognized by the immune system are called antigens. Antigens are usually protein fragments or carbohydrates.

During development, the immune system removes components that recognize “self”.

Immune response to one’s own body is called autoimmunity.

1. Physical barriers- skin, mucous membranes and their secretions- infection fighting chemicals,in tears, saliva, other

body fluids

2. Nonspecific - Innate defenses- phagocytosis - (engulfing cells)- inflammatory response- fever- anti-microbial proteins

complement, collectins, cytokines

3. Specific response - Acquired Immunity- Humoral immune response

- B cells, antibodies, memory cells- Cellular immune response

- T cells, cytokines, memory cells

Bacteria Viruses

Acquired response

Mucous membranes

Physical barriers

CiliaInnate response Cytokines

Antimicrobial secretionsMacrophages

Macrophagespresent antigens

Cellular response

T cells Cytokines

Cytotoxic T cells

Humoral response

B cells

Memory B cells

Plasma cells

Antibodies

Inflammatory response

A non-specific response triggered by

- injury - penetration of bacteria

-skin, respiratory, digestive, urinary or reproductive tract

 Two main players

- histamine- complement  

Histamine- dilates local blood vessels- increases capillary permeability

Result is redness, heat and swelling

heat - unfavorable to microorganisms- mobilizes white blood cells (monocytes)- raises metabolic rate of surrounding cells

Complement - chemotaxsis agent- recruits in WBC to injury site

The Inflammatory Response- starts with release of histamine and other chemicals- ends with WBC cleaning up the debris

Complement System

- chemical defense system that kills microorganisms- named the complement system because of the way

it works together with the immune system

- are a series of proteins, C1, C2 , etc 

- C5-C9 - form a large multi-protein complex- MAC - membrane-attack complex

MAC - inserts itself into the membrane of invading microorganisms- creates a pore- disrupts control of ion balance - cells burst

Anti-microbial chemicals on the non-specific response  - collectins

- recognize the sugar moieties present on the surface of foreign cells

- cytokines - interferons (chemical scouts), alert other cells to the presence of invaders

- also anti-viral

- interleukins (fever)- high temp - kills some infecting bacteria- lowers blood iron levels

- tumor necrosis factor

Specific, Adaptive Immunity - Acquired Response

Invoked when the inflammatory response and complement systems fails- Requires stimulation.- Response time is in days.

Major features:• Diversity - many different pathogens recognized• Specificity - distinguishes particular molecules• Memory - responds faster with subsequent exposure

Primary immune response is reaction to first exposure.

Secondary immune response is reaction to exposure using “memory” of first response.

Antibodies  - antibodies are proteins that bind to antigens - antigens - a protein or other molecule that causes antibody

productionantibody generators

- antibodies are produced by B cell

B-cells - type of lymphocyte- matures in the bone marrow- circulates in the blood and lymph system- encounters an antigen - makes a specific antibody- each B-cell produces only one antibody - clonal

 B- cells are the lymphocytes that mediate the Humoral response (antibody-directed immunity).

T cell lymphocytes.

- target and destroy infected body cells- develop in the bone marrow- differentiate into mature T cells in the Thymus gland- T cells move in the circulation and the lymphatic system

- are responsible for the Cellular Response (cell-mediated immunity).

Antibody-mediated and cell-mediated immune systems work together.

Humoral response -Antibody-directed Immunity Three basic steps

- detect the antigen- activate helper T cells- make the antibodies

Antigens activate B cells directly and indirectly

HOWEVER - indirect is the major pathway.

Antigen-presenting macrophage activates helper T cell

Role of helper T cells in the humoral response

- Recognize antigens presented by macrophages

- Stimulate B cells to produce antibodies

Antibodies

- several different classes - known as immunoglobulins, IgG, IgM, IgE, etc

Antibody structure

• Antibodies minimally consist of four proteins

• Two long proteins = heavy chains

• Two shorter proteins = light chains

• Constant region of each protein is similar in all antibodies.

• Variable region of each protein is diverse.

• Antigen binding sites are pockets where antigen is held.

• Idiotypes are sites in direct contact with antigen.

• The portion of the antigen contacting the antibody is called the epitope.

Problem

- humans produce billions of different types of antibodies

- Where are the genes?

- B cell antibody genes undergo a tremendous number of recombination events

- recombination occurs during B cell maturation

Simplest antibody

2 H (heavy) and 2 L (light) chains

random recombination can make 30,000 different H chains

random recombination can make about 3600 light chains

30,000 x 3600 = 108 million combinations- other processes generate more than 100 trillion

 - a particular B cells produces only one antibody- as it divides

- its daughter cells produce the same antibody

- it is these mature daughter cells that are circulating

Cell-mediated immunity - helper T cells

- recruit and activate B cells to make antibodies

- suppressor T cell - inhibit immune reaction - are off switches

- killer T cells- destroy infected body cells- cytotoxic T cells - a subset of killer T cells

- memory T cells - T cells ready to respond to make other T cells when antigen is reintroduced

Cytotoxic T cells can destroy cancer cells

Join T cell surface receptorsto bind antigen

Cell transport is disrupted and cell dies

The immune system is capable of memory

- referred to as secondary immunity

Vaccines

- work by triggering a primary immune response- with development of secondary immunity

- boosters - increase the number of memory cells present

- vaccines present an antigen that is derived from, or is highly related to that of, potential bacterial and viral invaders

 Blood types

- are determined by cell surface antigens - more than 30 known antigens on RBC plasma membranes

- blood transfusions - certain antigens must be matched are you elicit

an immune response - being treated like the massive foreign invasion

- two groups of antigens are of major significance- ABO system - Rh

ABO blood group

The I gene encodes enzymes that attach cell surface molecules on the sugar chains of red blood cells.

A allele attaches antigen A

B allele attaches antigen B

O allele no attachment performed

Blood type incompatibility

A person with type A blood who is transfused with type B blood will have antibodies that recognize and destroy the red blood cells carrying type B.

Type O is the universal donor.Type AB is the universal recipient.

Rh factor

Rh factor or rhesus factor is another blood group affecting cell surface molecules.

Phenotypes: Rh+ - produces Rh factor on RBCRh- - no Rh factor on RBC

Rh incompatibility occurs when an Rh- mother has an Rh+ child.

- hemolytic disease of the newborn - HDN - HDN occurs with the second pregnancy

- preventable through screening and anti-Rh+ therapy

Human leukocyte antigens (HLA)

HLA proteins are produced by major histocompatibility complex (MHC) class I and II genes.

Link sugars to form branched glycoproteins on cell surface of white blood cells.

HLA glycoproteins can recognize bacterial and viral proteins, marking them for immune system to target, a process called

antigen processing.

Antigen Presenting Cells

Cells which bind antigens with HLA glycoproteins are called antigen presenting cells.

Two types of antigen presenting cells are:

MacrophagesLymphocytes

Organ transplants

- need to match histocompatibility antigens between donor and recipient

-only 1 in 10,000 unrelated people will share a HLA type by chance at the six major HLA genes. (twins 100%, siblings 25%)

- matching at least 4 major HLA genes is needed for most transplants to succeed.

- HLA genes account for about 50% of the genetic impact on immunity.

HLA gene complex- consists of several gene clusters- class I HLA-A, HLA-B, HLA-C- class II HLA-SR, HLA-DQ, HLA-DP

- each gene in each class has multiple alleles

- haplotype- this is a set of alleles at a specific location- each of us has an specific array of HLA alleles on a given copy of chromosome 6

- since we have two copies of chromosome 6- each have two HLA haplotypes- population has millions of haplotypes

(allele combinations)

18,000 organ transplants/yr in US

- about 40,000 qualified patients (on the list)- about 3000/yr die while on the waiting list

estimated – about 50,000 transplant/yr is what is need xenotransplants

- animal –human transplant- transgenic pigs

therapeutic cloning

Xenografts

HLA and disease There is a relationship between certain HLA antigens and specific diseases Ankylosing spondylitis Inflammatory condition in which the vertebrae are inflamed and deformed, leading to fusion of the joints in the spine.

- Those with HLA-B27 are 100 times more likely to have this disease.- 90% of those afflicted carry HLA-B27 (versus 5% of general pop)

- maybe triggered by a bacterial infection Klebsiella However,

- 10% of cases do NOT have B27.- Not all with B27 allele get disease.

•=> HLA-B27 is a significant factor but not the sole factor in ankylosing spondylitis.

Why do we have a complicated HLA system?

Need to be able to recognize self from non-self

During development - immune system learns who is “self”

- a large group of diseases is related to the inability to differentiate “self”

- immune system has decided that a cell of our body is not of our body

Autoimmune Diseases

When the immune system attacks the tissues of an individual’s own body it is called autoimmunity. Autoantibodies recognize “self” proteins.

Some mechanisms include:

- Viruses use host proteins on the viral cell surface. These host proteins become the target of the immune

system which responds as if they are viral proteins.

- Thymocytes which recognize “self” antigens survive instead of apoptosing.

- Nonself antigen may coincidentally resemble “self” antigens.

Autoimmune disorder Symptoms

Target of Antibodies

Glomerulonephritis Lower back pain Kidney cell antigen that resembles Streptococcus antigen

Graves disease Restlessness, weight loss, irritability, increased heart rate and blood pressure

Thyroid gland antigen

Myasthenia gravis Muscle weakness Nerve message receptors on skeletal muscle cells

Pernicious anemia Fatigue and weakness Binding site for vitamin B on cells lining stomach

Rheumatoid arthritis Joint pain and deformity Cells lining joints

Systemic lupus erythematosus

Red rash on face, fever, weakness and kidney damage

DNA, neurons, blood cells

Type I diabetes Thirst, hunger, weakness, emaciation

Pancreatic beta cells

Ulcerative colitis Lower abdominal pain Colon cells

Inherited immune deficiencies

Mutations in genes encoding proteins used in immunity result in impaired immune response.

20 types of inherited immune deficiency

Chronic granulomatous disease: mutation of oxidase enzyme results in neutrophils that cannot kill bacteria.

Severe combined immune deficiency (SCID) impacts both humoral and cellular immunity due to lack of mature B cells and/or T cells.

X-linked agammaglobulinemia (XLA)

- usually boys- characterized by having multiple serious bacterial infection

during childhood (20 or more in 5 years).- have normal T cells - patients don’t have any mature B cell

- can't make antibodies

- protected for the first 6 months by maternal antibodies

- rest of life always having severe infectionspneumonia and strep

SCID - severe combined immunodeficiency

Both antibody-mediated and cell-mediated immune responses are non-functional

- usually die at a young age from a minor bacterial threat

“boy in the bubble”- David – died at age 12- lacked of a thymus gland

-Some SCID cases are due to ADA deficiency

(adenosine deaminase) - target disease for gene therapy

AIDS Acquired immunodeficiency syndrome

- collection of disorders that develop as a result of infection with HIV

- HIV , human immunodeficiency virus (retrovirus).

- virus infects macrophages and T4 helper cell

Problem - T cell activation also activates viral replication- with time, the helper T cells are killed off

- eventually loose ability to activate the antibody-mediated immune response result - increased susceptibility to infection and certain forms of

cancer - early death

Structure of HIV

HIV is an RNA virus (a retrovirus).

The RNA molecule encodes a reverse transcriptase enzyme which synthesizes a DNA copy of the RNA virus.

The virus is enclosed within a capsid within a coating of envelope protein studded with glycoproteins that can bind cell surface molecules on the host cell.

HIV envelope proteins gp41 and gp120 bind to CD4 and CCR5 receptors on the helper T cell.

Final note on AIDS:

its not that the immune system can’t fight the HIV infection, it just can’t keep up

- early HIV infections- produce 2 billion new B and T cell per day

- virus does two things- produces millions to billions of new virus per day- it mutates very rapidly

- antibodies useful today – no effect tomorrow

Treatment of HIV infection

• Drug therapies have cut the mortality rate from AIDS in half since 1996.

• Two reverse transcriptase inhibitors and a protease inhibitor are commonly used.

• Reverse transcriptase inhibitors block conversion of the viral RNA into DNA.

• The protease inhibitor limits the processing of several viral proteins required for new particle formation.

Resistance to AIDS?

Are some individuals less susceptible to AIDS than others?

People at high risk for HIV infections (individuals with multiple partners or hemophilia) who are not infected more often have a CCR5 receptor gene with a 32-base deletion. This deletion truncates the protein and prevents localization to the cell surface.

Long term nonprogressors are infected but healthy.

Correlated with heterozygous carriers of CCR5 deletion.

Correlated with milder inflammation response.

Disorders of the Immune system Allergies

- overreactions of the immune system- weak antigens are called allergens

- house dust, pollen, cat dander food, medicines

- up 10% of us have at least one allergy

Problem relates to Immune response memory

Mast cell release histamine - local inflammatory response

- if histamine enter blood stream in high amounts- full body response - anaphylaxis- treat with antihistamines- epinephrine

Asthma

- a chronic disease involving contraction of the respiratory airways, inflammation and mucus production in the lungs. Breathing becomes difficult during an asthma attack. Some asthma attacks are triggered by allergic reactions.

Allergic response

Humoral and cellular arms respond. IgE class antibodies are made and bind mast cells.

Mast cells release allergy mediators like histamine and heparin that cause inflammation, runny eyes and nose, rashes and asthma.

Allergens activate a class of helper T cells which release cytokines.

Severe allergic reaction throughout the body is called anaphylatic shock and can be life-threatening.