Hypersensitivity Reactions

The purpose of the immune response is to protect against invasion by foreign organisms, but they often lead to host tissue damage.  An exaggerated immune response that results in tissue injury is broadly referred to as a hypersensitivity reaction.

 Classification:

a.  According to Gell and Comb’s classification, hypersensitivity reactions can be divided into four types (type I, II, III, and IV) depending on the mechanism of immune recognition involved and on the inflammatory mediator system recruited.

b.  Types – I II, and III reactions are dependent on the interaction of specific antibodies with the given antigen, whereas, in type IV reactions recognition is achieved by antigen receptors on T-cells.

1) Type I hypersensitivity (anaphylactic or immediate type) reaction

Definition:  Type I hypersensitivity reaction may be defined as a rapidly developing Immunologic reaction occurring, within minutes after the combination of an antigen with antibody bound to mast cells or basophilic in individuals previously sensitized o the antigen. 

The reactions depend on the site of antigen exposure for example in skin – hive, upper respiratory tract – Hay fever, bronchial asthma and systemic reaction – anaphylactic syndrome

 Pathogenesis:

-Presentation of the antigen (allergen) to precursor of TH2cells by antigen presenting dendritic cells on epithelial surfaces 

-  Newly minted TH2 cells produce clusters of cytokines including IL-3,IL-4,IL-5 and GM-CSF

-  The IL-4 is essential for activation of B cells to produce IgE and IL-3 and IL-5 are important for the survival of eosinophillic activation

-  The IgE antibodies produced has a high affinity to attach to mast cells and basophiles

-  A mast cell or basophil armed with cytophilic IgE antibodies is re-exposed to the specific allergen  

-  In this process multivalent antigens binds to more than one IgE molecules and cause cross-linkage with adjacent IgE antibody. 

-  This bridging of IgE molecules activates signal transduction pathways from cytoplasmic portion of IgE fc receptors. This signal initiates two parallel but independent processes. One leading to mast cell degranulation with discharge of preformed (primary) mediators and the other involving denovo synthesis and release of secondary mediators.  

(I)  Mast cell degranulation discharge preformed granules such as primary mediators including biogenic amines, histamine,  adenosine, eosinophilic and neutrophilic chemotactic factors, enzymes including proteases, and several acid hydrolases.

(II)  The other involved is de novo synthesis and release of secondary mediators such as arachidonic metabolites

- Leukotrienes C4 & D4 – most potent vasoactive and spasmogenic agents known by – highly chemotactic for neutrophiles, eosinophils and monocytes

- Prostaglandin D2 – causes  intense bronchospasm & increase mucus secretion

-  Platelet-activating factor release histamine, ↑ed  vascular permeability

-  Cytokines—activation of inflammatory cells

-  Thus, type I reactions have two well-defined phases.

a.  Initial phase (response): 

-  Characterized by vasodilatation, vascular leakage, and depending on the location, smooth muscle spasm or glandular secretions.

b.  Late phase 

-  As it is manifested for example in allergic rhinitis and bronchial asthma,  more intense infiltration of eosinophiles, neutrophiles, basophilic, monocytes and CD4 + T cells are encountered and so does tissue destruction (epithelial mucosal cells). 

-  Mast cells and basophiles are central to the development of Type I reaction.

Mast cells are bone marrow driven cells widely distributed in tissues around blood vessels, and sub epithelial sites where type I reaction occurs. 

Morphology:

-  Histamine and leukotrienes are released rapidly from sensitized mast cells and are responsible for intense immediate reaction characterized by edema, mucous secretions and smooth muscles spasms.

-  Others exemplified by leukotrienes platelet activating factor (PAF), TNF-α and cytokines are responsible for the late phase response by recruiting additional leukocytes, basophilic neutrophiles and eosinophils.  These cells secrete other waves of mediators and thus, damage epithelial cells.

-  Eosinophiles are particularly important in the late phase. The armamentarium of eosinophils is as extensive as the mast cells.

-   Prototype example of Morphologic features in type l reactions is exemplified by bronchial asthma with

-Increased mucous glands with resultant mucous secretion

-Hypertrophy of bronchial smooth muscles with attending bronchoconstriction

-Edema formations with inflammatory cells infiltrations peribronchially

2) Type II hypersensitivity reaction

Definition: Type II hypersensitivity is mediated by antibodies directed towards antigens present on the surface of exogenous antigens.

Three different antibody-dependent mechanisms are involved in this type of reaction

(i) Complement-dependent reaction

 i. Direct lysis:

a) It is effected by complements activation, formation of membrane attack complex (C5 –9). This membrane attack complex then disrupts cell membrane integrity by drilling a hole. In annucleate cells once and in nucleated cells many attacks of the complex are needed for cell lysis, because the latter ones have abilities to repair cell membrane injuries rapidly. 

b)  Opsonization: By C3b, fragment of the complement to the cell surface enhances phagocytosis.

Examples include red blood cells, leukocytes and platelets disorders: Transfusion reaction; haemolytic anemia; Agranuloytosis; Thrombocytopenia; Certain drug reaction

 ii. Antibody dependent cell - mediated cytotoxicity /ADCC/

-  This type of antibody mediated Cell injury  does not involve fixation of complements.

The target cells coated with IgG antibodies are killed by a variety of nonsensitized cells that have Fc receptors. 

-  The non-sensitized cells included in ADCC are monocytes/large granular/ lympholytes / Natural killer cells, neutrophils and eosinophils. 

-  The cell lysis proceeds without phagocytosis. Example include graft rejection

 iii. Antibody-mediated cellular dysfunction 

- In some cases, antibodies directed against cell surface receptors impair or dysregulated function without causing cell injury or inflammation. For example: In Myasthenia Gravis, antibodies reactive with acetylcholine receptors in the motor end plates of skeletal muscles impair  neuromuscular transmission and cause muscle weakness. 

-  The converse is noted in Graves disease where antibodies against the thyroid-stimulating hormone receptor on thyroid epithelial cells stimulate the cells to produce more thyroid hormones.  

 3) Type III hypersensitivity / immune complex-mediated

 Type III hypersensitivity reaction is induced by antigen-antibody complex that produces tissue damage as a result of their capacity to activate the complement system. The antibodies involved in this reaction are IgG, IgM or IgA.

Sources of antigens include:

a. Exogenous origin Bacteria –streptococcus (infective endocarditis) Viruses –Hepatitis B virus (Polyarteritis nodosa) Fungi – Actinomycetes (farmer’s lung) Parasites –plasmodium species (glomerulonephritis) Drugs – quinidin (hemolytic anemia) Foreign serum (serum sickness)

b. Endogeneous origin 

Nuclear components (systemic lupus erythematosis) Immunoglobulins (rheumatoid arthritis) Tumour antigen (glomerulonephritis) Therefore, autoimmune diseases are hypersensitivity diseases in which the exaggerated immune response is directed against the self antigens as exemplified by the above three diseases.

The pathogenesis of systemic immune complex diseases has three phases:

 a.  Formation of Ag-Ab complex 

-  Introduction of an antigen into the circulation, then Production of specific antibodies by immuno-competent cells and subsequent antigen antibody formation

b.  Deposition of immune complexes 

-  The mere formation of antigen-antibody complex in the circulation does not imply presence of disease.  

Immune deposition depends on: 

i)  Size of immune complexes. Large complexes in great antibody excess are rapidly removed by mononuclear phagocytic system (MPS).Most pathogenic ones are of small or intermediate size / formed in slight Ag excess/ 

ii)  Functional status of MPS: MPS clears circulating immune complexes however, its overload or dysfunction increase the persistence of immune complexes in circulation and resulting in tissue depositions. 

Other factors for immune deposition include charge of immune complexes, valence of antigen, avidity of the antibody, affinity of the antigen to various tissue components, three-dimenstional /lattice/ structure of the complex, hemodynamic factors, etc.

Sites of immune complex deposition include:

Renal glomeruli, joints, skin, heart, serosal surfaces,  & small blood vessels

c. Inflammatory reaction 

-  After immune complexes are deposited in tissues acute inflammatory reactions ensues and the damage is similar despite the nature and location of tissues. Due to this inflammatory phase two mechanisms operate

i) Activation of complement cascades:

- C-3b, the opsonizing, and -C-5 fragments, the chemotaxins are characterized by neutrophilic aggregation, phagocytosis of complexes and release of lysosomal enzymes that result in necrosis.-C3a, C5a – anaphylatoxins contribute to vascular permeability and contraction of smooth muscles that result in vasodilation and edema-C5-9 – membrane attack complexes formation leads to cell lysis (necrosis) 

ii)  Activation of neutrophiles and macrophages through their Fc receptors. Neutrophiles and macrophages can be activates by immune complexes even in absence of complements.  With either scenario, phagocytosis of immune complexes is effected with subsequent release of chemical mediators at site of immune deposition and subsequent tissue necrosis.

Morphology of immune complex-mediated hypersensitivity reaction

-  The morphologic consequences are dominated by acute necrotizing vasculitis with intense neutrophilic exudation permitting the entire arterial wall. Affected glomeruli are hyper cellular with proliferation of endothelial and mesengial cells accompanied by neutrophilic and mononuclear infiltration. Arthritis may also occur.

Classification of immune complex-mediated diseases:

Immune complex-mediated diseases can be categorized into systemic immune complexes diseases (e.g. serum sickness) and localized diseases (e.g.Arthus reaction). 

 Systemic immune-complex diseases: 

-  Acute forms: If the disease results from a single large exposure of antigen / ex: acute post-streptococal glomerulonephritis and acute serum sickness/ all lesion then tend to resolve owing to catabolism of the immune complexes. 

 Arthus reaction:

-  The Arthur reaction is defined as a localized area of tissue necrosis resulting from an immune complex vasculitis usually elicited in the skin. Arthus reaction occurs at site of inoculation of an antigen and depends on the presence of precipitating antibody in the circulation / with antibody excess/ that resulted in immune complex deposition. Inflammatory reaction develops over 4-8 hours and may progress to tissue necrosis as described above.

-  Chronic forms of systemic immune complex diseases  result from repeated or prolonged exposure of an antigen. Continuous antigen is necessary for the development of chronic immune complex disease. Excess ones are most likely to be deposited in vascular beds. 

Clinical examples of systemic immune complex diseases:

Various types of glomerulonephritis

Rheumatic fever

Various vasculitides

Quartan nephropathy

Systemic lupus erytomatosis

Rheumatoid arthritis

 4) Type IV hypersensitivity (Cell-mediated) reaction

 Definition: The cell-mediated type of hypersensitivity is initiated by specifically sensitized T-lymphocytes. It includes the classic delayed type hypersensitivity reactions initiated by CD4+Tcell and direct cell cytotoxicity mediated by CD8+Tcell. Typical variety of intracellular microbial agents including M. tuberculosis and so many viruses, fungi, as well as contact dermatitis and graft rejection are examples of type IV reactions

The two forms of type IV hypersensitivity are: 

1.  Delayed type hypersensitivity:  this is typically seen in tuberculin reaction, which is produced by the intra-cutaneous injection of tuberculin, a protein lipopolysaccharide component of the tubercle bacilli. 

Steps involved in type lV reaction include

a.  First the individual is exposed to an antigen for example to the tubercle bacilli where surface monocytes or epidermal dendritic (Langhane’s) cells engulf  the bacilli and present it to naïve CD4+ T-cells through MHC type ll antigens found on surfaces of antigen presenting cells (APC),

b.  The initial macrophage (APC) and lymphocytes interactions result in differentiation of CD4+TH type one cells

c.  Some of these activated cells so formed enter into the circulation and remain in the memory pool of T cells for long period of time.

d.  An intracutanous injection of the tuberculin for example to a person previously exposed individual to the tubercle bacilli , the memory TH1 cells interact with the antigen on the surface of APC and are activated with formation of granulomatous reactions

 2. T-cell mediated cytotoxicity

In this variant of type IV reaction, sensitized CD8+T cells kill antigen-bearing cells. Such effector cells are called cytotoxic T lymphocytes (CTLs). CTLs are directed against cell surface of MHC type l antigens and it plays an important role in graft rejection and in resistance to viral infections. It is believed that many tumour-associated antigens are effected by CTLs. Two mechanisms by which CTLs cause T cell damage are:

-  Preforin-Granzyme dependant killing where perforin drill a hole into the cell membrane with resultant osmotic lysis and granzyme activates apoptosis of the target cells

-  FAS-FAS ligand dependant killing which induce apoptosis of the target cells .

References

Bezabeh ,M. ; Tesfaye,A.; Ergicho, B.; Erke, M.; Mengistu, S. and Bedane,A.; Desta, A.(2004). General Pathology. Jimma University, Gondar University Haramaya University, Dedub University.