The Human Immune System

Video

What is the immune system?

The bodys defense against disease causing organisms, malfunctioning cells, and foreign particles

The First Line of Defense

~Skin~
- The dead, outer layer of skin, known as the epidermis, forms a shield against invaders and secretes chemicals that kill potential invaders - You shed between 40 50 thousand skin cells every day!

The First Line of Defense

~Mucus and Cilia~
- As you breathe in, foreign particles and bacteria bump into mucus throughout your respiratory system and become stuck - Hair-like structures called cilia sweep this mucus into the throat for coughing or swallowing

Dont swallowed bacteria have a good chance of infecting you?

The First Line of Defense

~Saliva~
Whats the first thing you do when you cut your finger? - Saliva contains many chemicals that break down bacteria - Thousands of different types of bacteria can survive these chemicals, however

The First Line of Defense

~Stomach Acid~
- Swallowed bacteria are broken down by incredibly strong acids in the stomach that break down your food - The stomach must produce a coating of special mucus or this acid would eat through the stomach!

Think of the human body as a hollow plastic tube

The food is digested within the hole in the tube, but it never actually enters into the solid plastic material.
Tube inner surface ~Digestive System~ Tube outer surface ~Skin~ Plastic interior ~Body~

Escherichia coli is common and plentiful in all of our digestive tracts. Why are we all not sick?
- These bacteria are technically outside the body and aid in digesting material we cannot - Only if E.Coli are introduced in an unnatural manner can they break through the first line of defense and harm us

The Second Line of Defense

~White Blood Cells~

- If invaders actually get within the body, then your white blood cells (WBCs) begin their attack - WBCs normally circulate throughout the blood, but will enter the bodys tissues if invaders are detected

Video

White Blood Cells ~Phagocytes~

These white blood cells are responsible for eating foreign particles by engulfing them Once engulfed, the phagocyte breaks the foreign particles apart in organelles called ________ Lysosomes

Where could invaders hide from phagocytes?

Phagocytosis
If cells are under attack they release histamine. Histamine plus chemicals from pathogens mean neutrophils are attracted to the site of attack. Pathogens are attached to antibodies and neutrophils have antibody receptors. Enodcytosis of neutrophil membrane phagocytic vacuole. Lysosomes attach to phagocytic vacuole pathogen digested by proteases

The Second Line of Defense

~Interferon~

- Virus-infected body cells release interferon when an invasion occurs

- Interferon chemical that interferes with the ability to viruses to attack other body cells

What happens to already infected cells?

White Blood Cells ~T-Cells~

T-Cells, often called natural killer cells, recognize infected human cells and cancer cells T-cells will attack these infected cells, quickly kill them, and then continue to search for more cells to kill

Neutrophils
60% of WBCs Patrol tissues as they squeeze out of the capillaries. Large numbers are released during infections Short lived die after digesting bacteria Dead neutrophils make up a large proportion of puss.

Macrophages
Larger than neutrophils. Found in the organs, not the blood. Made in bone marrow as monocytes, called macrophages once they reach organs. Long lived Initiate immune responses as they display antigens from the pathogens to the lymphocytes.

Lymphocytes
Produce antibodies B-cells mature in bone marrow then concentrate in lymph nodes and spleen T-cells mature in thymus B and T cells mature then circulate in the blood and lymph Circulation ensures they come into contact with pathogens and each other

B -Lymphocytes
There are c.10 million different Blymphocytes, each of which make a different antibody. The huge variety is caused by genes coding for abs changing slightly during development. There are a small group of clones of each type of B-lymphocyte

B -Lymphocytes
At the clone stage antibodies do not leave the Bcells. The abs are embedded in the plasma membrane of the cell and are called antibody receptors. When the receptors in the membrane recognise and antigen on the surface of the pathogen the Bcell divides rapidly. The antigens are presented to the B-cells by macrophages

The Second Line of Defense

~The Inflammatory Response~

- Injured body cells release chemicals called histamines, which begin inflammatory response
- Capillaries dilate - Pyrogens released, reach hypothalamus, and temperature rises - Pain receptors activate - WBCs flock to infected area like sharks to blood

Two Divisions of the Immune System

- The efforts of the WBCs known as phagocytes and T-cells is called the cellmediated immune system.
- Protective factor = living cells
- Phagocytes eat invaders - T-cells kill invaders

Two Divisions of the Immune System

The other half of the immune system is called antibody-mediated immunity, meaning that is controlled by antibodies This represents the third line of defense in the immune system

The Third Line of Defense

~Antibodies~

- Most infections never make it past the first and second levels of defense - Those that do trigger the production and release of antibodies
- Proteins that latch onto, damage, clump, and slow foreign particles - Each antibody binds only to one specific binding site, known as an antigen

Antibody Production
- WBCs gobble up invading particles and break them up - They show the particle pieces to T-cells, who identify the pieces and find specific B-cells to help - B-cells produce antibodies that are equipped to find that specific piece on a new particle and attach

Video - 1:58

Type

Number of ag binding sites

2

Site of action

Functions

IgG

Blood Tissue fluid CAN CROSS PLACENTA

Blood Tissue fluid Secretions (saliva, tears, small intestine, vaginal, prostate, nasal, breast milk)

Increase macrophage activity Antitoxins Agglutination

Agglutination

IgM

10

IgA

2 or 4

Stop bacteria adhering to host cells Prevents bacteria forming colonies on mucous membranes

IgE

Tissues

Activate mast cells HISTAMINE Worm response

Immunity
- New particles take longer to identify, and a person remains ill until a new antibody can be crafted - Old particles are quickly recognized, and a person may never become ill from that invader again. This person is now immune.

What is immunity?
- Resistance to a disease causing organism or harmful substance - Two types
- Active Immunity - Passive Immunity

Active Immunity
- You produce the antibodies
- Your body has been exposed to the antigen in the past either through:
- Exposure to the actual disease causing antigen You fought it, you won, you remember it - Planned exposure to a form of the antigen that has been killed or weakened You detected it, eliminated it, and remember it
What is this second type of exposure called?

Vaccine
Antigens are deliberately introduced into the immune system to produce immunity Because the bacteria has been killed or weakened, minimal symptoms occur Have eradicated or severely limited several diseases from the face of the Earth, such as polio and smallpox

How long does active immunity last?

It depends on the antigen Some disease-causing bacteria multiply into new forms that our body doesnt recognize, requiring annual vaccinations, like the flu shot Booster shot - reminds the immune system of the antigen Others last for a lifetime, such as chicken pox

Passive Immunity
You dont produce the antibodies
A mother will pass immunities on to her baby during pregnancy - through what organ? Placenta These antibodies will protect the baby for a short period of time following birth while its immune system develops. What endocrine gland is responsible for this? Thymus Lasts until antibodies die

Why doesnt the mother just pass on the WBCs that remember the antigens?

Immune Disorders
~Allergies~
- Immune system mistakenly recognizes harmless foreign particles as serious threats - Launches immune response, which causes sneezing, runny nose, and watery eyes - Anti-histamines block effect of histamines and bring relief to allergy sufferers

Asthma
Attacks can occur at any time Genes play a role in who develops asthma Breathing becomes difficult, sufferers experience wheezing, coughing, a tightness about the chest and shortage of breath. 1/7 children in UK has asthma, number is increasing. >1000 people die each year from asthma every year in the UK

Asthma
Airways in asthmatics are always inflamed, during an attack this worsens. Fluid leaks from blood into airways and goblet cells secrete lots of mucus Airways can become blocked Muscles surrounding trachea and bronchioles contract which narrows airways further

Asthma
Vaccines are being developed to make allergic responses less severe Designed to desensitise people so they do not produce antibodies to allergens Genetic tests may be used to screen children and then a vaccine could be given to prevent them developing asthma

Immune System Disorders

Hypersensitivity (Allergy): An abnormal response to antigens.

Four Types of Hypersensitivity Reactions:

Type I (Anaphylactic) Reactions

Type II (Cytotoxic) Reactions

Type III (Immune Complex) Reactions Type IV (Cell-Mediated) Reactions

Type I (Anaphylactic) Reactions

Occur within minutes of exposure to antigen Antigens combine with IgE antibodies IgE binds to mast cells and basophils, causing them to undergo degranulation and release several mediators:
Histamine: Dilates and increases permeability of blood vessels (swelling and redness), increases mucus secretion (runny nose), smooth muscle contraction (bronchi). Prostaglandins: Contraction of smooth muscle of respiratory system and increased mucus secretion. Leukotrienes: Bronchial spasms.

Anaphylactic shock: Massive drop in blood pressure. Can be fatal in minutes.

Mast Cells and the Allergic Response

Type II (Cytotoxic) Reactions

Involve activation of complement by IgG or IgM binding to an antigenic cell. Antigenic cell is lysed. Transfusion reactions:
ABO Blood group system: Type O is universal donor. Incompatible donor cells are lysed as they enter bloodstream. Rh Blood Group System: 85% of population is Rh positive. Those who are Rh negative can be sensitized to destroy Rh positive blood cells.
Hemolytic disease of newborn: Fetal cells are destroyed by maternal anti-Rh antibodies that cross the placenta.

Type III (Immune Complex) Reactions

Involve reactions against soluble antigens circulating in serum. Usually involve IgA antibodies. Antibody-Antigen immune complexes are deposited in organs, activate complement, and cause inflammatory damage.
Glomerulonephritis: Inflammatory kidney damage.

Occurs with slightly high antigen-antibody ratio is present.

Type IV (Cell-Mediated) Reactions

Involve reactions by TD memory cells.
First contact sensitizes person. Subsequent contacts elicit a reaction.

Reactions are delayed by one or more days (delayed type hypersensitivity).

Delay is due to migration of macrophages and T cells to site of foreign antigens.

Reactions are frequently displayed on the skin: itching, redness, swelling, pain.
Tuberculosis skin test Poison ivy Metals Latex in gloves and condoms (3% of health care workers)

Anaphylactic shock may occur.

Aquired Immune Deficiency Syndrome

Caused by the Human Immunodeficiency Virus Discovered in 1983 Specifically targets and kills T-cells Because normal body cells are unaffected, immune response is not launched

AIDS
~The Modern Plague~

- The HIV virus doesnt kill you it cripples your immune system - With your immune system shut down, common diseases that your immune system normally could defeat become life-threatening - Can show no effects for several months all the way up to 10 years

Opportunistic Oral Yeast Infection by Candida albicans in an AIDS Patient

Source: Atlas of Clinical Oral Pathology, 1999

Chest X-Ray of AIDS Patient with Tuberculosis

Extensive tumor lesions of Kaposiss sarcoma in AIDS patient. Source: AIDS, 1997

Chronic Herpes Simplex infection with lesions on tongue and lips. Source: Atlas of Clinical Oral Pathology, 1999.

Non-Hodgkins Lymphoma & ascites in AIDS patient Source: Tropical Medicine and Parasitiology, 1997

What happens when the bodys lymphocytes fail to recognize its own cells and tissues as such?

Autoimmune Diseases
Failure of autoantibodies and T cells to recognize own cells Autoantibodies and T cells launch attack against own cells Perhaps due to overactive or an overabundance of helper T lymphocytes

 Possible Causes:
Inefficient lymphocyte programming Self proteins circulate without having been exposed to system
(ex: sperm, eye lens, thyroid)

Potential Treatments:
Control inflammation

(ex: diabetes mellitus)

Immunosuppressive Medication

(ex: corticosteriods, cyclosporin, methotrexate)

Therapeutic Antibodies against specific T cell molecules

Reactions between selfantigens and antibody production against foreign antigens

(with fewer side effects)

Examples of Autoimmune Diseases

Multiple sclerosis Myasthenia gravis Crohns disease Graves disease Type 1 Diabetes mellitus Rheumatoid arthritis Psoriasis Scleroderma Systemic lupus erythematosus

Systemic Lupus Erythematosus Criteria (4 or more)

1. 2. 3. 4. 5. 6. Butterfly rash Discoid lupus Photosensitivity Oral ulcers Arthritis Serositis 7. Neurologic dis 8. Hematologic dis 9. Renal disorder 10. Immunologic dis: LE cell, anti-DNA, antiSm, false pos STS 11. Anti-nuclear antibody

Systemic Lupus Erythematosus

Incidence 1:2500 Female: male 10:1 2nd/3rd decade of life More common and severe in Blacks Skin, kidney, serosal membranes, joints, heart Many autoantibodies Failure to maintain self-tolerance

Systemic Lupus Erythematosus

Genetic factors
30% concordance in monozygotic twins Increased risk in family members HLA-DQ locus and SLE association Inherited deficiency of complement and SLE

Non-Genetic factors
Drugs: procainamide, hydralazine Sex hormones (estrogens>androgens)\ UV light

Systemic Lupus Erythematosus Morphology

Acute necrotizing vasculitis Skin rash (erythematous/maculopapular) Discoid lupus: disc-shaped patches on skin Serosa: pericardium, pleura Cardiovascular: valvular endocarditis Kidney: glomerulonephritis Joint: swelling of synovial membranes; bones ok Central nervous system: microinfarcts

Systemic Lupus Erythematosus: Clinical Course

Variable Flare-ups/ remissions Steroids; immunosuppressive drugs Renal transplantation

Rheumatoid Arthritis
Proliferative synovitis Destruction of articular cartilage: disabling Extra-articular lesions of skin, heart, blood vessels, lungs, muscles (similar to SLE, SS) Prevalence 1%; starts in 4th/5th decade of life Female: male 3-5:1 Genetic predisposition with microbial initiation Rheumatoid factor: anti-IgG Fc Juvenile rheumatoid arthritis

Rheumatoid Arthritis

Osteoarthritis

Spondyloarthropathies
Ligamentous attachments to bone affected Sacroiliac joints; uveitis Absence of RF HLA-B27 association Ankylosing spondylitis, Reiters syndrome (urethritis, conjunctivitis) Infectious assoc: Yersinia, Shigella, Salmonella, Helicobacter, Campylobacter

Sjogrens Syndrome
Keratoconjunctivitis sicca (dry eyes) Xerostomia (dry mouth) Immune-mediated destruction of lacrimal and salivary glands Primary: sicca syndrome HLA-DR3 Secondary: with RA, SLE, etc. HLA-DR4 Women >40 yo B cell lymphoma in 1% Pseudolymphoma in 10%

Sjogrens Syndrome

xerostomia and xerophthalmia

Systemic Sclerosis
Inflammation /fibrosis of interstitium of organs Skin: fingers, upper extremities, shoulders, neck,face GI: esophagus, difficulty swallowing Musculoskeletal: joints and muscles Lungs: diffuse interstitial fibrosis Kidneys, Heart Raynauds phenomenon: reversible vasospasm Limited variant: CREST syndrome

Scleroderma: Skin patch

Other Autoimmune Disorders

Inflammatory myopathies
Dermatomyositis Polymyositis

Mixed connective tissue disease

Features not characteristic of other dis Anti-RNP Little renal disease

Immunodeficiencies
Primary
X-linked agammaglobulinemia (Bruton) Common variable ID (heterogeneous group; M&F) Isolated IgA deficiency Hyper IgM syndrome DiGeorge syn: Thymic hypoplasia Severe combined ID

Secondary
AIDS Lymphatic malignancy

Laboratory Tests for HIV

EIA screen for HIV1 and HIV2 Confirmatory western blot RT-PCR qualitative for HIV1 HIV viral load in serum HIV genotype: predicts resistance to drugs HIV phenotype: measures resistance to drugs CD4 and CD8 counts

Amyloidosis
Organ deposition
Kidney, spleen, liver, heart, endocrine

Diagnosis
Rectal/gingival biopsy Congo red stain Serum/urine protein electrophoresis

Prognosis poor

Systemic sclerosis (SS)

interstitial tissue of various organs - inflammation and fibrosis in 95% skin (scleroderma) sometimes visceral lesions (GI tract, lungs, kidneys, heart, muscles) = most important F:M=3:1 any age (childhood - old age), mainly 3.-5. decade, rare histologically: sclerosis of collagen (loss of filamentous structure, homogenization, hyalinization, no nuclei)

 skin - fingers - progression proximally first edema, than sclerosis of collagen, atrophy of epidermis, loss of skin adnexa skin is dry, with smooth surface, shiny, thin - ulceration loss of elasticity, rigidity spontaneous amputations, mask face

GI tract namely esophagus - atrophy and fibrosis of the wall - problems with swallowing Locomotory apparatus loss of mobility, rigidity
Lungs interstitial fibrosis Heart interstitial fibrosis of myocardium Vessels Raynaud's phenomenon - polyarteritis nodosa

Polymyositis (dermatomyositis)
symetrical muscle weakness, pain, swelling, atrophy 2 peaks of incidence - 5-15 y., 50-60 y. frequently combination with other systemic diseases - overlap syndromes, vasculitis mixed connective tissue disease

Polyarteritis (periarteritis) nodosa

necrotizing inflammation of the wall of middle sized and small arteries - necrotizing vasculitis deposition of immuncomplexes (similar to Arthus's phenomenon) often segmentally (uninvolved skipped areas) thrombosis - infarctions variable clinical presentation - most frequently kidneys, heart, liver, GIT (perforation!), lungs rarely!

Polyarteritis (periarteritis) nodosa

histologically: fibrinoid necrosis (eosinophillic), infiltration by neutrophillic leucocytes, microaneurysms - rupture or thrombosis infarction healing by scar (fibrous tissue) M:F=2:1 (!predominance of males!) Dx. based on histology - diagnostic excision

Wegener's granulomatosis
rare acute necrotizing arteritis (similar to polyarteritis nod.) - kidneys, respiratory tract (lungs), spleen acute granulomatous inflammation, necrotizing namely respiratory tract (nose, paranasal sinuses, larynx, trachea, bronchi, lungs) necrotizing progressive Glnf. - in the past fatal, today cytostatics