Immunopathology - The Hypersensitivities

Review Chapter 15 - Type I and Type II Hypersensitivity Reactions

Read the introduction

Type II Reactions – Cytotoxic Reactions mediated by IgG and IgM

Caused by antibodies react with antigens on the surface of target cells.  See Figure 15.1:

Complement gets activated and the cells lyse. Activated complement also promotes inflammation.

Also, cells coated with IgG (not IgM) can be destroyed byWBC’s bearing Fc receptors.  This is called Antibody Dependent  Cell-mediated Cytotoxicity (ADCC).

Sometimes, antibody binding to cell surface receptors, can cause target cells to change function:

 

Myasthenia gravis – an auto-antibody reacts with the acetylcholine receptor at the neuromuscular junction. This blocks the binding of the neurotransmitter (acetylcholine) and thus stops neural stimulation of the muscle. (This is known as antagonism).   The result is severe muscle weakness – including difficulty in chewing, swallowing and breathing.

Graves’ Disease – Autoantibody reacts with a hormone receptor on thyroid cells.  This autoantibody binds to the thyroid stimulating hormone (TSH) receptor  and this stimulates the thyroid cells and they become over-active.  (The antibody in this case is called an agonist which results in hyperthyroidism).    

Some important TypeII reactions:

Transfusion Reactions – antibody to blood group antigens  cause the lysis of the transfused blood.  The lysis is actually caused by activated complement.

The Rh system merits special mention.  Please read the section on Rh incompatibility Reaction. 

The Rh antigen is called the D antigen. Rh-negative people don’t naturally have anti-D antibodies, but they quickly develop them if they become immunized.

There are two ways that Rh-negative people become immunized with D(+) rbc’s.

1.     Rh-negative woman pregnant with anRh-positive child.  The child’s RBC’s leak into the mother particularly during childbirth.  This immunizes the mother and subsequent pregnancies are at risk because the anti-D antibodies easily cross the placenta.  These destroy the red cells of the developing fetus  and the newborn.  Hence the name: erythroblastosis fetalis or hemolytic disease of the newborn.

Human anti-D antibody is given to prevent  this problem.  How might this work?

2.     An Rh-negative person, shown to be negative for anti-D antibodies, is given Rh-positive blood in an emergency situation where  an Rh-compatible blood can’t be found.

Other cytolytic reactions caused by antibody:

For unknown reasons (idiopathic) or often as a consequence of certain infectious disesase and malignancy,some people make autoantibodies to their redcells, and other cell types and tissues.  If the RBC’s are being targeted the syndrome is called autoimmune hemolytic anemia.  If platelets are involved the syndrome is called thrombocytopenia purpura.

Certain drugs bind to particular cells and become immunogenic in some people, provoking the synthesis of antibodies and the destruction of the cells to which the drugs are attached.

 Type III Reactions --- Immune Complex Reactions

Antigen + Antibody complexes form and are deposited in to tissues, activating complement , attracting inflammatory cells and provoking damage.  The damage can be local or systemic.  Serum sickness is the prototype disease.

Certain types of infection are prone to causing Type III problems : 

·      Group A strep has a variety of antigens that are cross-reactive with self-antigens present in human heart muscle, cartilage and the glomerular basement membrane.

·      Mycobacterium leprae, malaria, dengue fever may cause circulating immune complexes

Also some autoimmune diseases  have a type III hypersensitivity component. :

·      Systemic lupus erythmatosis,  (SLE)– attacks many organs of the body and causes fever, joint pain, damage to the central nervous system, heart and kidneys.  Patients make antibody against  cell nuclei :

o      Anti-nuclear antibodies (ANA)

o      Anti-dsDNA

o      Anti-ssDNA

o      Anti-histones

Immune complexes get trapped in the glomeruli, triggering inflammatory reactions and damage.

·      Rheumatoid arthritis – Many patients (70%) make rheumatoid factor, an IgM anti-IgG.  Other immune mechanisms are also involved including Th1 cells, Tc cells, activated macrophages and NK cells. 

·      Goodpasture’s syndrome – antibodies are made against the basement membrane of the lungs and kidneys.  Severe inflammation can lead to pulmonary hemorrhage and glomerulonephritis.

·      Pemphigus vulgaris – antibodies against desmosomes.  Type II and type III reactions  cause the skin and mucous membranes to erode.

Review Chapter 16 – Type IV, Delayed Hypersensitivity

This Hypersensitivity is often said to be mediatied by Cell Mediated Immunity since it can transferred to animals with transfusions of T-cells but not serum.  Therefore, there is no antibody involved.

The prototype reaction is the Tuberculin Skin Test.  Tuberculin is also called PPD or Purified Protein Derivative of Mycobacterium tuberculosis.

The basic reaction is shown in Fig. 16.1.

Note that T_H1 cells, get activated and release a number of cytokines especially IFN-g and IL12.  Macrophages and other inflammatory cells get attracted.    These can accumulate in large numbers.  If enough accumulate the lesion may turn into a granuloma – almost like a tumor of accumulated macrophages and lymphocytes. 

Contact sensitivity to poison ivy and certain metals is Type IV hypersensitivity.

Certain autoimmune diseases have a Type IV hypersensitivity component:

·      Multiple sclerosis – Th1 cells coordinate an attack the myelin sheath of neurons in the central nervous system resulting in a progressive paralysis.

·      Type I Insulin dependent diabetes mellitus – T-cells attack the insulin producing b-cells of the pancreas’ islands of Langerhans. 

·      Hashimoto’s Thyroiditis – Hypothyroidism resulting from the progressive destruction of the gland by a T-cell orchestrated attack.  Early in the course there is goiter which later disappears as the thyroid atrophies.