Humoral Immune Responses

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Humoral Helper (Th2) T Cell Responses

Mature naive B cells have IgM and IgD antibodies on their surface. When these B cells encounter an antigen complementary to their immunoglobulin receptor, they bind to the antigen and endocytose the receptor/antigen complex. The antigen is then degraded in the endosome. Next processed peptide binds to the cleft in the MHC-II and the peptide/MHC-II complex is expressed on the cell surface. When the B cell encounters a helper (Th2) T cell that is specific to the peptide/MHC-II complex, nonspecific cell adherence occurs until the TcR and peptide/MHC-II complex are brought into contact (Note: The processed peptide that the TcR recognizes may be different from the epitope the antibody receptor binds). Once this occurs, interaction between the TcR and the peptide/MHC-II complex tranduces signals to the interior of the helper T cell. This causes the helper T cell to express CD40 ligand on its surface that binds to CD40 on the B cell shifting the B cell into the cell cycle causing B cell proliferation. In addition to upregulating CD40 ligand on its surface, the Th2 cell secretes IL-4 that synergizes with the CD40 ligand to cause B cell clonal expansion. Next the Th2 cell secretes IL-5 and IL-6 that stimulate B cell differentiation. As the stimulated B cells leave the secondary lymphoid tissue they interact with follicular dendritic cells (FDC). CD23 on the FDC binds CD19 on the B cells. If a B cell receives no further stimulation, it develops into a plasma cell while if it contacts CD40 ligand it becomes a memory cell. The antibody initially produced is all of the IgM isotype, but dependent on the amounts of IL-4, IL-5, IFN-y, and TGF-p (transforming growth factor p) secreted by the T cell the B cell undergoes isotype switching and becomes dedicated to producing either IgA, IgE, or one of the subclasses of IgG. Once the antibody is secreted by the plasma cells it circulates throughout the body. Antibody can neutralize the antigen preventing infection of more cells, opsinize antigen increasing the efficiency of phagocytosis, or become involved in ADCC.

If any of the costimulatory signals described in the above responses are lacking, the effector cell may become anergic. This prevents inappropriate activation of immune cells such as cells that are specific to self antigens. This is referred to as peripheral tolerance.

Hypersensitivity Reactions

Hypersensitivity reactions occur when the body mounts an excessive immune response to a typically innocuous antigen resulting in tissue damage. Hypersensitiv-ity reactions require a sensitizing exposure so the excessive response does not occur with the initial exposure. There are four classic hypersensitivity reactions. Types I, II, and III occur shortly after reexposure to the antigen and are therefore called immediate hypersensitivity reactions. Type IV reactions on the other hand occur days after reexposure to the incitng antigen so they are referred to as delayed-type hypersensitivity reactions. Once sensitized the reactions often worsen in severity with each subsequent exposure due to increased antibody or T cell production.

Type I reactions occur within seconds or minutes after exposure to the antigen. Antigens that provoke this type of reaction are usually small, soluble proteins capable of eliciting an immune response at low doses (examples: pollen, pet dander, penicillin). After the initial exposure to the antigen, Th2 helper cells direct B cells to become IgE producing plasma cells. Monomers of IgE antibody specific to the inciting antigen then bind to FceRI on mast cells with high affinity. Upon reexposure to the antigen the IgE on the mast cell binds to the antigen causing aggregation and subsequent crosslinking of the FceRI resulting in degranulation. Mast cell degranulation releases histamine, leukotrienes, and cytokines that cause smooth muscle contraction, capillary dilatation, and increased vascular permeability. The severity of the clinical presentation is dependent on the amount of antigen innoculum, route of antigen exposure, and the amount of IgE produced. Cutaneous exposure to limited amounts results in a flare and wheal. Intravenous innoculation may result in systemic anaphylaxis that should be treated with epinephrine. Inhalation of the antigen may cause allergic rhinitis or asthma. Patients with reactions that are not life threatening can be treated with antihistamines for symptom relief, and the later sequelae can be treated with corticosteroids. Patients can be desensitized to the antigen by controlled exposure that shifts the antibody produced from an IgE to IgG and IgA decreasing the likelihood that receptor crosslinking and subsequent degranulation will occur since the IgG and IgA will compete with IgE making FceR aggregation less likely.

Type II reactions occur a few hours after exposure to the antigen. Antigens that cause this type of reaction bind to cell surfaces. After initial exposure to the antigen, IgG antibodies are formed. Upon reexposure to the antigen, memory cells in the bone marrow become activated and a large amount of antigen specific IgG is produced. This IgG then binds to antigen on the surface of host cells. Some IgG then fixes complement initiating the complement cascade and the Fc portion of some of the IgG binds to Fc receptors on macrophages and neutrophils. Activation of the complement cascade and phagocytic cells results in destruction of the cells to which the antigen is adherent. RBCs and platelets are typically the targets of this type of reaction.

Type III reactions occur several hours after antigen exposure. The antigens responsible for these reactions are usually soluble. When there is antibody in excess compared to antigen, insoluble immune complexes form while the complexes are soluble if there is antigen excess. Upon repeat exposure to the antigen, memory cells are activated resulting in production of large amounts of antibody that then form complexes with these antigens. These small complexes then become deposited in various tissues. Soluble complexes are widely distributed while particulate complexes tend to become deposited near the site of antigen entry. Deposited complexes activate complement and phagocytic cells. Since phagocytes cannot phagocytize the deposited complexes, they release their granular contents rather than engulfing the particles and tissue damage results. Clinical presentation is dependent on the route of exposure to the antigen. If the antigen is injected into the skin, IgG diffuses into the soft tissue, and immune complexes are formed which activate complement resulting in the release of vasoactive and chemotactic mediators. Release of factors such as C5a allows immune cells and fluid to enter the area from the vasculature. Complement and granular contents from immune cells cause tissue damage. This is referred to as the Arthus reaction. Inhalation of an antigen can cause an intrapulmo-nary Arthus reaction with the classic example being Farmer's lung when an individual inhales actinomycetes from mouldy hay. Serum sickness occurs when a large dose of antigen is given intravenously with horse serum antivenin being the classic example. After antigen exposure the immune complexes that form are dispersed to joints, renal glomeruli, and vessel walls as well as other sites. About eight days after the injection the patient becomes febrile, lymph nodes and joints swell, an urticarial rash appears, and the patient develops proteinuria.

Type IV hypersensitivity also referred to as contact hypersensitivity occurs one to three days after antigen exposure. In contrast to the immediate hypersensitivity reactions that are mediated by the formation of antibodies (i.e., Th2 mediated response), delayed hypersensitivity is mediated by Th1 helper cells. Antigens that elicit this type of response are capable of forming stable complexes with host proteins making them antigenic. The altered host protein is then endocytosed, processed by the cell, and expressed on the cell surface with MHC-II. Reexposure to the antigen activates previously sensitized Th1 (CD4) cells that enter the site where the antigen is located. Antigen presenting cells then present the processed antigen/MHC-II complex to the helper T cells that stimulates these cells to release various cytokine mediators resulting in fluid and immune cell influx into the area. Examples of this type of reaction include the response to gliadin (celiac disease), pentadecacatechol (poison ivy), and tuberculin (Mantoux reaction/PPD skin test). Alternatively, type IV reactions can be mediated by CD8 T cells recognizing processed antigen in association with MHC-I that activates their cytotoxic action.

Autoimmune Disease and Immunodeficiency

In addition to the excessive responses that produce hypersensitivity, inappropriate and inadequate responses occur resulting in either autoimmune disease or immunodeficiency. The occurrence of either type of reaction is infrequent, but they are worth mentioning because they show how the immune system should normally function.

Autoimmune diseases occur when the adaptive immune system mounts a sustained response against self antigens resulting in long term tissue damage. Autoanti-bodies can cause destruction as in the case of autoimmune hemolytic anemia. Autoantibodies can also be stimulatory. In Grave's disease antibodies to the thyroid stimulating hormone receptor are formed which stimulate thyroid hormone release resulting in thyrotoxicosis. Autoantibodies can also cause hypofunction of an organ. In myasthenia gravis antibodies form against the acetylcholine receptor on motor end plates causing the receptor to become depleted which results in muscle weakness. In systemic autoimmune diseases such as systemic lupus erythematosus and rheumatoid arthritis a myriad of autoantibodies form as well as altered cell mediated immunity result in tissue damage characteristic of each of these diseases.

In immunodeficiency the body fails to respond appropriately to eradicate an infection. In chronic granulomatous disease the cytochrome b oxidase system of phagocytic cells is defective so they are incapable of forming reactive oxygen intermediates to destroy engulfed pathogens. These patients have chronic infections with Staphylococcus aureus, candida, and aspergillus being the organisms that trouble these patients most. In hereditary angioedema, individuals lack activated C1 inhibitor and this results in recurrent episodes of acute edema mediated by C2a. Also patients

Table 2.1. Cytokines and their actions

Cytokine Primary Sources

Actions

Table 2.1. Cytokines and their actions

IL-1

Macrophages

Pyrogen, T cell activator, and macrophage

and epithelial cells

activator

IL-2

T cells

T cell growth factor

IL-4

T cells and mast cells

B cell activator and induces isotype switching

to IgE

IL-5

T cells and mast cells

Eosinophil growth factor

IL-6

T cells and

T cell and B cell growth and differentiation;

macrophages

stimulates production of acute phase proteins

in the liver

IL-8

Macrophages

Chemotactic agent for neutrophils

IL-12

Macrophages

Activates NK cells and stimulates Th1

differentiation of CD4 T cells

IL-13

T cells

B cell growth and differentiation

IFN-y

T cells and NK cells

Activates macrophages and increases MHC

expression

IFN-a

Leukocytes

Inhibits viral replication and increases MHC-I

expression

IFN-ß

Fibroblasts

Inhibits viral replication and increases MHC-I

expression

deficient in any component of the MAC, the terminal component of the complement system, have been shown to be prone to Neisserial infections. In Bruton's Y-globulinemia, an X-linked syndrome, individuals produce limited amounts of im-munoglobulin because of defective heavy chain gene rearrangement. These individuals have recurrent infections with staphylococci, streptococci, and hemophilus. Individuals with DiGeorge syndrome lack sufficient numbers T cells because their thymus failed to develop appropriately from the third pharyngeal pouches. These individuals have no cell-mediated responses and humoral responses are depressed. Affected individuals also lack parathyroid glands and have cardiovascular abnormalities. The most pervasive immunodeficiency is severe combined immunodeficiency (SCID). In these individuals defective recombinase enzymes prevent formation of T- and B cell receptors thus they are very susceptible to all infectious agents. These patients can be treated with a bone marrow transplant if a compatible donor is available. Despite the fact that these disorders are very uncommon they do illustrate the importance of an intact and appropriately functioning immune system.

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