Immune pathology

Hypersensitivity Reactions:

Inappropriate responses by immune system to environmental agents that would pose no health risk. 

These agents provoke immune reaction - allergens (i.e. antigens that promote allergic responses)

Typically, they are proteins or other large complex organic molecules provoking immediate responses but almost any foreign substance has potential to be an allergy for someone

E.g. Small organic molecules, any synthetic inorganic molecule or even metals.

Four classifications

I.        Type I allergic responses:

 

(1)   First exposed to particular “antigen” (allergen-pollen, fungal, animal fur etc.).

·         Immune response is provoked – primary immune response, No inflammatory reaction

-         IgE Antibodies are produced

-         IgE Antibodies binds to mast (Tissue WBC’s) or basophils (Blood cells) cell surfaces.

 

(2)   Subsequent exposure to same allergen

·         Allergen binds to IgE antibodies triggering the mast cell to release chemical mediators of inflammation: histamines, leukotrienes etc.

-         Histamine: cause vasodilation, ↑ capillary permeability & other inflammatory response (smooth muscle [] & broncho [], ↑ mucus secretion)

-          

Usually localized response to localized exposure.

·         Mucous membrane & sinus: Allergy rhinitis 

·         Typical allergy involving Swollen/thickened mucosa (rhinitis), obstructed sinus, watery mucus discharge, often general fatigue, discomfort

·         Seasonal allergies to pollen or fungal spores but they may be perennial responses to things - house dust, dust mites, animal dander (hair & skin cells) or commonly feathers.    

·         Bronchial airways: allergic asthma

·         Mucosa of airway swells, ↑secretion,

·         the airways are narrowed as part of the response

·         Gut: Food allergies 

·         local responses involving IgE sensitized mast cells in the intestinal mucosa

·         localized inflammation in Gut

·         can lead to diarrhea & vomiting

·         Skin: Atopic dermatitis allergies

·         swelling, redness, itchiness of skin,

·         formation of hives (urticaria)

·         Elevated wheals that develop as fluids accumulate in local tissue in response to histamine. They are very red & pruritic.

·         Anaphylactic reactions

·         Systemic; Instead of IgE sensitized mast cells being localized, it is all over the body.

·         On second or subsequent exposure to the allergen

-        Massive release of histamines

Systemic vaso][

Drastic ¯ in BP (shock).

-        ↑ leukotrienes

severe broncho [] ® occluding airways. Oxygen intake ¯

Brain can’t get enough oxygen, nutrients ® fall, collapse ® Death.

·         Allergens of anaphylactic reactions: peanuts/peanut butter, shellfish, bee, wasp venoms.

·         The best protection is to avoid the allergens & always carry an EpiPen (epinephrine dose) to self-administer on first recognition of symptoms.

 

 

II.      Type II reactions - cytotoxic reactions.

·         They result from antibodies (IgG & IgM) reacting to cell surface antigens to cause cells to agglutinate or lyse & also complement activation.

·         ABO & Rh incompatibility reactions.

·         A blood type A - type A antigen & type B antibody. During blood transfusion, if type B antigen blood is given, agglutination occurs in blood ® ¯ RBC + ↑ Blood clumps

 

III.        Type III reactions - Immune Complex reactions 

·         Initial expose to antigen ® antibody production however, those antibodies will combine with antigens & the complex turn into insoluble in blood, comes out of the blood & Binds to endothelial cells – lining of blood vessel

Stimulate inflammatory response

-        In Kidney: ¯ in glomerulus filtration ® APSGN (Acute Post Streptococcal Glomerulonephritis)

-        In Heart Valves: puffin of heart valves of they no longer work ® Stenosis – lead to permanent alteration in shape of heart valves - replacing valve. 

-        lupus (Systemic Lupus Erythematosus):

·         This response may also be seen in response to drugs

E.g. the antibiotic penicillin & some insect venoms leading to rashes, edema & urticaria.

 

IV.        Type IV or Cell-mediated reactions 

·         Different from the previous three reactions in that it does NOT involve an antibody response

·         Reaction is mediated by T-lymphocytes (Cell-mediated reaction)

·         Directly bind with antigen: cause slower reaction

·         localized & long term

·         Delayed hypersensitivities because it usually takes 24-72 hours for the response to fully develop.

·         Tuberculin (TB) test that indicates previous sensitization or exposure

·         Contact dermatitis which is a local skin response to allergens

?          Dermatitis: skin irritation

-         E.g. Poison Ivy: release poison oak oil, which is a major irritant, response to when our body reacts with type 4 hypersensitivity. Whenever oil is contacted ® severe rash formation. The more you scratch, the more it spreads. When burned, the oil gets vaporized & when in haled, can be very dangerous. 

·         Contact pneumonitis in which the allergen is inhaled thus affecting the lung tissue.

-         "Farmer Lung " for example results from breathing in fungal spores from moldy hay.    

?          Pneumonitis: a general term that refers to inflammation of lung tissue.

 

Rejection of Tissue Transplant

·         On cells of our body, we have a cluster of proteins called MHC’s (Major Histocompatibility Complexes).

·         Unique to individual

·         “Self” cell identifiers.

-         If a cell does not possess right MHC then WBC will engulf & destroy it & initiate a primary immune response. 

·         During tissue transplant if the MHC does not match that of the receivers

·         Immune system tries to destroy it

·         Matching closely minimize rejection.

·         The only way this procedure works is by taking immunosuppressant drugs (antirejection drug)

·         Corticosteroids, cyclosporin – derived from microorganism

·         Drug must be taken for rest of life

·         Discontinuation of drug may lead ↑ immune response against transplanted tissue.

·         Downside of corticosteroid & cyclosporin: ¯ general immunity ® ↑susceptibility to infections. 

3 levels of transplant rejection

1.    Hyperacute Rejection:  not common

·         Rejection response immediately after the transplant – when blood flow begins into the new transplanted tissue – immediate organ failure.

·         Occurs when recipient was previously exposed to MHC/antigen similar to their donor’s MHC – like blood transfusion

Secondary immune response is set to respond.

·         Signs of rejection

Organs discolor ® Not function normally ® Organ destroyed (Need to be removed)

 

 

2.    Acute Rejection: common

·         This reaction occurs within weeks to months of the transplant surgery – typically developing within the first week.

·         primary immune response

·         Reason

(1)    too much difference b/w MHC

(2)   Immunosuppressed drugs were not effective enough

(3)   Individual was noncompliance with medication adherence.

Leads to deterioration of organ to a point where it needs to be replaced/ it fails

?          Noncompliance: failure to act in accordance with a wish or command.

?          Adherence: commitment to a person, cause, belief.

 

3.    Chronic Rejection

·         This occurs usually many months to years after the transplant

·         Reason

·         Slow gradual response to the foreign tissue (after all the immune system is not entirely suppressed).

·         Gradually cells die and are replaced by fibrous connective tissue & the organ function slowly declines until it reaches a point of ineffectiveness & which point a new transplant is required.

Exception of Rejection of tissue transplant-Organ is not a problem

·         Cornea

-       Tissues are avascular so that the immune system cannot reach them.

-       Largely Acellular protein matrix

·         Fetal tissues

·         They do not yet display MHC’s on their cell surfaces (otherwise their mother would reject them in utero). 

·         Auto graft/ auto transplant

-       Use of own tissue / cells to replace where required

1)     Skin

2)     Stem cells.

·         Pig Heart

-       Use gene of MHC, insert it into fertilized egg of an animal so that the animal will display the same MHC as the ones inserted. Those organs can now be considered as a “self” when they develop transplant from these organs will not cause a reaction due to exact MHC match.

-       Problem: pathogens have moved from 1 species to another can transfer disease.

 

Immune Deficiencies:

This can involve the loss of function for any of the components of the immune system.

1.    Primary immunodeficiencies: rare

·         Born with the deficiency

·         Genetic defect or error in congenital development.

®      some error in development led to not having particular component of immune system.

?          Congenital: present from birth.

·         Wide range of deficiencies

®      ¯ antibody production

®      Deficiencies in production of specific WBC types

®      Inability to produce any complement protein

·         Gene therapy: provide genes required for the missing components.

 

2.    Secondary deficiencies: much common

·         Causes

(1)   Long term corticosteroid use: (glucocorticoid®immunosuppression)

(2)   Long term use of cyclosporin:

®      Anti rejection drug taken post organ transplant

(3)   Protein malnutrition/alcohol abuse:  ¯ synthesis of complement protein in liver

®      Protein malnutrition ® ¯ complement production by liver

®      Alcohol abuse ® kidney damage.

liver function lead to ¯ complement protein production & kidney diseases lead to loss of antibodies or complement can ¯ level of immune function.

(4)   Part of immune system is targeted

®      Autoimmune problem: immune system attacks another part of self immune system

®      HIV (viral infection): virus attack certain parts of immune system

§  Macrophage

§  T-lymphocytes: ¯ T-lymphocytes ® decreased immune regulation & ¯ cell mediated immunity.

(5)   Exposure to radiation (especially affecting bone marrow)

(6)   Environmental chemicals (e.g. benzene, some pesticides).

(7)   Deficiency of B-lymphocytes

®      inadequate antibody production (hypogammaglobulinemia)

 

·         Immunodeficiency disorders

The main problem with all immunodeficiency disorders is prone to opportunistic infections.

Organisms that are common in the environment and normally pose no real threat can suddenly become major risks.

·         Fungus Candida albicans: cause thrush

?          Thrush: yeast infection

·         Fungus Pneumocystis carinii: cause pneumonia

·         E. coli of our normal flora become invasive.

Generally, this susceptibility requires continued use of prophylactic drugs such as antibiotics.  

It is currently believed that cancer changes to the common cells are a common phenomenon but that our immune system does constant surveillance & detects abnormal cells early & destroys them thus preventing the development of cancer.

This has led to the concept of immunotherapy as a cancer treatment involving the boosting of the immune system to heighten its response to abnormal cells. - Certainly, reduced immunity can boost the risk of some cancers significantly.

·         Kaposi's sarcoma, an otherwise very rare cancer, that becomes very common in individuals with AIDS.

HIV (Human Immunodeficiency Virus) &AIDS (Acquired Immuno-Deficiency - Syndrome)

·         First founded as AIDS

·         1982

·         Discovered the cause as virus

·         Haitian & Gay men’s disease

·         Originated from congo

·         AIDS is a disease that results from an infection by HIV

·         Retroviruses - they only contain RNA, NO DNA

There are two main strains

1)     HIV-1: the main infectious agent worldwide

2)     HIV –2: mainly found in West Africa but also scattered at lower frequencies in many other populations.

The two viruses cause similar effects, but HIV-2 develops symptoms more slowly and does not seem to spread as rapidly.

 

·         Pathway of HIV

·         viruses enter body & infect only specific cell types. Most notably they attack specific kinds of T-lymphocytes (regulatory cells, macrophages, monocytes), & neurons of the CNS.

·         They target T-lymphocytes & other cells that have CD4+ surface proteins that virus can bind to & thereby enter host cell. 

·         Transmission – Not easily transmitted

§  Via blood transfusion

Transfusion of contaminated blood

Reduce by

®      We can do donor screening & testing of for presence of HIV antibodies in donated blood

®      Use of universal precautions

§  Via needle stick injury

Direct transfer via blood, intravenous drug users at risk

Reduced by

®      Needle exchange program

®      Education

§  High risk of sexual transmission

Sex that break mucosal layer (e.g. rape, anal sex)

Reduced by

®      Safe sexual practice (latex condoms)

 

 

 

 

·         HIV in pregnancy

HIV can be transmitted from an infected mom to her baby via the placenta, during the tissue trauma of birth or through breast feeding.

 

·         Not easily passes through

·         17~20% of pregnancy where HIV positive mom can transfer it to the baby

·         Drug can be used to block the transfer down to 2-5%.

 

·         Tests for HIV is antibody based

If baby born to an HIV positive mom, baby may test positive

-       Has antibodies for HIV transferred via placenta

-       No actual virus

-       Test shows positive d/t natural passive immunity

-       When antibody wears out, test will come out negative.

 

·         Testing of HIV

: Test for antibodies of HIV – use enzymes/ electrophoresis

-          Can take several months before antibody is high enough to be testable.

-          Concerning for HCW who might have had needle stick injury due to duration.

 

§  The EIA (enzyme immunoassay) or ELISA (enzyme-linked immunosorbent assay) which detects presence of antibodies to HIV when antibodies bind to enzymes that lead to a colour change in a solution.

 

§  The Western Blot test is used as a follow up to a positive ELISA test. It uses electrophoresis to detect antibodies to specific viral antigens.

 

[Note – the above two tests detect the presence of antibody only. They are not direct tests for the presence of the virus. In combination however they are quite reliable indicators of infection]

 

§  Polymerase Chain Reaction (PCR)

Detect viral nucleic acids directly.

Uses enzymes that are derived from extremophile bacteria (archaea bacteria) It’s gene allow us to make restrictive enzymes where we can take a small piece of DNA & replicate it rapidly so that even if a small amount of viral RNA & DNA is present in sample, it can be multiplied significantly within a small period of time to be able to detect & identify it.

This test is useful for testing newborns from HIV positive moms & it has become the standard method of testing as it has gradually become less expensive to perform.

 

·         Long incubation period of HIV

 

When HIV enters the body,

1)    ↑ viral population

Initial signs & symptoms of HIV: flu-like/mononucleosis – fever, malaise, lethargy, nausea, sore throat, headaches, photophobia & swollen lymph nodes.

2)    ↑ Immune response

Immune system acts to gain control over the virus ® Resolve & no symptoms for years.

3)    ¯ viral load in body

4)    ¯ Immune response

5)    HIV gradually rises in levels in the infected individual despite tremendous effort on the part of the immune system to control it.

6)    Collapsed Immune system

Viral levels are high to significantly lower the levels of CD4 T-lymphocytes

we see symptoms of AIDS.

 

·         The HIV can only enter cells by binding to CD4 receptors

·         Only certain cells have CD4 Receptors

§  Macrophage

§  T-lymphocyte

§  Brain Cells (CNS neurons)

·         They attack the immune system ® ↑ sickness.

·         Individuals with AIDS commonly dies of infections that are a result of ¯ immunity.

§  PCP (Pneumocystis Carinii Pneumonia): microorganism is usually harmless as the immune system always controls it BUT ¯ immune response lead to lung failure. Growth of this fungus like microorganism in the lungs ® death.

§  Other opportunistic respiratory infections

§  High risk of rare cancer

Kaposi’s sarcoma: common in AIDs patient,  

 

·         HIV control drugs

·         Anti-retro viral drug: drugs that control RNA based viruses.

-         Stops viral replication

-         Turns HIV into a Chronic illness

-         Virus will always be present in body

-         But it will not turn into AIDS.

·         Disadvantage: evolution will favor selection of virus that can reject antiretroviral drug. Thus, a number of different drugs that function slightly differently in hopes that when it fails, the others won’t, resulting in death of virus ® thus, you need to be compliant in medication adherence. (has side effect, not everyone can tolerate)

 

AUTOIMMUNE DISEASES:

·         Autoimmunity is the immune system treats your own cells as non-self & tries to destroy them.

·         Currently there is no clear model for the cause - combination of genetic & environmental factors (e.g. prior infection by some viruses or bacteria or severe stress) seem to be generally involved. 

·         Significant cause for pathologies

-         Diabetes (Type 1) might be brought on by immune response against self-cells in the pancreas.

·         Effective treatments - immunosuppressive pharmaceuticals.

·         Autoimmune disorder

(1)   Systemic Lupus Erythematosus/ SLE

·         Autoimmune disease: attack own tissue & part of that response is the production of antibodies to self molecules leading to damage tissues (Type 3 hypersensitivity)

·         Tends to be widespread in targets.

-         Can attack any tissue/organ within the body

·         Make it hard to diagnose initially

-         Can give different symptoms for different cells that it targets

-         Could lead to a lot of unexplained tissue damage.

·         Common symptoms

-         Rashes: erythematosus of skin (around skin, nose)

-         Makes face look like wearing a wolf mask – thus “lupus”

-         Polyarthritis: symmetrical joint inflammation in the hands, wrists, elbows, shoulders, knees & ankles it does not usually involve joint erosion or deformity.

-         Pleurisy with chest pain d/t pleural membrane inflammation.

-         Glomerulonephritis d/t damage by the immune complexes to the glomeruli-pericarditis

?          Glomerulonephritis: inflammation of the glomeruli

-         Raynaud's syndrome involving painful vasospasm in the extremities (fingers and toes)

?          Raynaud’s syndrome: rare disorder of the blood vessels. Blood can’t get the surface of the skin & affected areas turn pale.

?          Vasospasm: narrowing of the arteries caused by

-         CNS effects such as depression, behaviour and mood changes, psychoses etc.

·         Exacerbated by certain chemicals

-         hair dye product

-         ↑ expose to UV rays of sun

?          Exacerbate: make worse

·         Blood markers can be detected in blood to diagnose lupus

-         Anti DNA antibodies

-         Anti nuclear antibodies

·         Fairly difficult to control

-         Immunosuppressants can be used but high risk of infection

·         More common in women than men

·         Progresses rapidly in younger people, Progresses slower in older patients

-         Develops gradually