Immunology - Hypersensitivity Types 3,4,5.pptx

Immunology - Hypersensitivity Types 3,4,5

1. Hypersensitivity Type III, IV, and V V. Dhanush Prabhakar I M.Sc Biotechnology 24BIOB002

2. Introduction Our immune system plays a crucial role in protecting our body against pathogens, but sometimes there is an exaggerated response . This exaggerated response is triggered by the interaction of the immune system with an antigen (allergen) and is referred to as hypersensitivity . Hypersensitivity reactions are classified into four types by Coombs and Gell . The symptoms typically appear in individuals who had at least one previous exposure to the antigen. Hypersensitivity reactions can be classified into four types: Type I - IgE mediated immediate reaction Type II - Antibody-mediated cytotoxic reaction (IgG or IgM antibodies) Type III - Immune complex-mediated reaction Type IV - Cell-mediated, delayed hypersensitivity reaction

3. Type III hypersensitivity reaction Type III hypersensitivity reaction involves IgG antibodies bound to foreign antigens in the blood. These antibody–antigen complexes can precipitate and get stuck in certain locations, such as blood vessels in the skin, kidneys and joints, where they activate the complement cascade to cause local damage. The most common diseases involving a type III hypersensitivity reaction are "serum sickness, post-streptococcal glomerulonephritis, systemic lupus erythematosus, farmers' lung (hypersensitivity pneumonitis), and rheumatoid arthritis". The principle feature that separates type III reactions from other hypersensitivity reactions is that in type III reactions, the antigen-antibody complexes are pre-formed in the circulation before their deposition in tissues. Most commonly, immune-complex reactions cause  palpable purpura, the hallmark of small-vessel vasculitis . These are visible, non-blanching haemorrhages that are raised and palpable on examination.

4. Mechanism of Immune-Complex Hypersensitivity In many situations, reactions between the various antigens and antibodies in the body give rise to formation of immune complexes. In the normal course, these immune complexes are normally removed by mononuclear-phagocyte system through participation of RBC . However, the body may be exposed to an excess of antigen in many conditions, such as persistent infection with a microbial organism, autoimmunity to self-components, and repeated contact with environmental agents. When the clearance capacity of this system is exceeded, deposition of the complexes takes place in various tissues . Immune complexes are deposited ( a ) on blood vessel walls, ( b ) in the synovial membrane of joints, ( c ) on the glomerular basement membrane of the kidneys, and ( d ) on the choroid plexus of the brain. Sometimes, immune complexes are formed at the site of inflammation itself. These  in situ  immune complexes, in certain cases, may be beyond the reach of phagocytic clearance and hence aggregate and cause disease . Immune complexes fix complement and are potent activators of the complement system. Activation of the complement results in the formation of complement components, such as C3a- and C5a-anaphylatoxins that stimulate release of vasoactive amines. The C5a attracts neutrophils to the site, but these neutrophils fail to phagocytose large aggregated mass of immune complexes, and instead release lysosomal enzymes and lytic substances that damage host tissue.

5. Manifestations of Immune-Complex Hypersensitivity Arthus reactions Arthus reaction is an inflammatory reaction caused by deposition of immune complexes at a localized site. This reaction is named after Dr. Arthus who first described this reaction. This reaction is edematous in the early stages, but later can become hemorrhagic and, eventually, necrotic. The lag time between antigen challenge and the reaction is usually 6 hours . This is considerably longer than the lag time of an immediate hypersensitivity reaction, but shorter than that of a delayed hypersensitivity reaction. Tissue damage is caused by deposition of antigen–antibody immune complexes and complement. The activation of complement through its product of activation causes vascular occlusion and necrosis . Serum sickness Serum sickness is a systemic inflammatory reaction caused by deposition of immune complexes at many sites of the body. The condition manifests after a single injection of a high concentration of foreign serum . It appears a few days to 2 weeks after injection of foreign serum or certain drugs, such as penicillin. However, serum sickness is considered as an immediate hypersensitivity reaction, because symptoms appear immediately after formation of immune complex. Unlike type I hypersensitivity reaction, a single injection acts as both priming and shocking doses. Fever, lymphadenopathy, rashes, arthritis, splenomegaly, and eosinophilia are the typical manifestations. Disease is self-limited and clears without sequelae.

6. Immune-Complex Diseases  Formation of circulating immune complexes contributes to the pathogenesis of a number of conditions other than serum sickness. These include the following:   1. Autoimmune diseases   · Systemic lupus erythematosus (SLE)   ·  Rheumatoid arthritis   2. Drug reactions   ·  Allergies to penicillin and sulfonamides   3. Infectious diseases   ·  Poststreptococcal glomerulonephritis   ·  Meningitis   ·  Hepatitis   ·  Infectious mononucleosis   ·  Malaria   ·  Trypanosomiasis SMALL VESSEL VASCULITIS SLE RHEUMATOID NODULES

7. Diagnosis of type III hypersensitivity reactions  Punch biopsies of the vasculitis rash typically show a leukocytoclastic reaction, in which there is superficial and mid perivascular neutrophilic infiltration with fibrinoid necrosis of the vessels and fibrin extravasation. Treatment of type III hypersensitivity reactions Removal of the offending agent is the mainstay of treatment of  type III hypersensitivity  reaction. Antihistamines and nonsteroidal anti-inflammatory drugs can provide symptomatic relief. Corticosteroids are used in severe cases to suppress inflammation. They are also used as premedication to prevent hypersensitivity from happening. Avoiding exposure to an allergen is critical to the management of HP. In addition, corticosteroids are helpful in patients with inflammatory features. SLE is treated based on the individual patient's disease condition. Hydroxychloroquine is essential for long-term treatment in all SLE patients. Antimalarials, corticosteroids, nonbiologic DMARDS, nonsteroidal anti-inflammatory, and biologic DMARDs are other medications used to treat SLE. Treatment of autoimmune disorders includes one or a combination of hydroxychloroquine, NSAIDs, azathioprine, cyclophosphamide, methotrexate, mycophenolate, and tacrolimus.

8. Type IV Delayed (Cell-Mediated) Hypersensitivity Type IV hypersensitivity reaction is called delayed type hyper-sensitivity (DTH) , because the response is delayed. It starts hours or days after primary contact with the antigen and often lasts for days. The reaction is characterized by large influxes of nonspecific inflammatory cells, in particular, macrophages . It differs from the other types of hypersensitivity by being mediated through cell-mediated immunity. This reaction occurs due to the activation of specifically sensitized T lymphocytes rather than the antibodies. Initially described by Robert Koch in tuberculosis as a localized reaction, this form of hypersensitivity was known as tuberculin reaction . Later, on realization that the reaction can be elicited in various pathologic conditions, it was renamed as delayed type hypersensitivity. Mechanism of DTH The DTH response begins with an initial sensitization phase of 1–2 weeks after primary contact with an antigen. TH1 subtypes CD4 are the cells activated during the sensitization phase. A variety of antigen-presenting cells (APCs) including Langerhans cells and macrophages have been shown to be involved in the activation of a DTH response. These cells are believed to pick up the antigen that enters through the skin and transport it to regional lymph nodes, where T cells are activated by the antigen. The APCs present antigens complexed in the groove of major histocompatibility complex (MHC) molecules expressed on the cell surface of the APCs. For most protein antigens or haptens associated with skin DTH, CD4 1  T cell s are presented with antigens bound to MHC class II alleles, human leukocyte antigen (HLA)-DR, HLA-DP, and HLA-DQ. Specific MHC class II alleles are recognized to produce excessive immune activation to antigens.

9. On subsequent exposure, the effector phase is stimulated. The TH1 cells are responsible in secreting a variety of cytokines that recruit and activate macrophages and other non-specific inflammatory cells. The response is marked only after 2–3 days of the second exposure . Generally, the pathogen is cleared rapidly with little tissue damage. However, in some cases, especially if the antigen is not easily cleared, a prolonged DTH response can itself become destructive to the host, as the intense inflammatory response develops into a visible granulomatous reaction .

10. Types of DTH Reactions Contact hypersensitivity Contact hypersensitivity is a manifestation of DTH occurring after sensitization with certain substances. These include drugs, such as sulfonamides and neomycin ; plant products, such as poison ivy and poison oak ; chemicals, such as formaldehyde and nickel ; and cosmetics, soaps and other substances. This reaction manifests when these substances acting as haptens enter the skin and combine with body proteins to become complete antigens to which a person becomes sensitized. On second exposure to the same antigen, the immune system responds by attack of cytotoxic T cells that cause damage, mostly in the skin. The condition manifests as itching, erythema, vesicle, eczema, or necrosis of skin within 12–48 hours of the second exposure. Tuberculin-type hypersensitivity reaction Tuberculin reaction is a typical example of delayed hypersensitivity to antigens of microorganisms, which is being used for diagnosis of the disease. Tuberculin skin test:  This test is carried out to determine whether an individual has been exposed previously to  Mycobacterium tuberculosis  or not. In this test, a small amount of tuberculin (PPD) , a protein derived from the cell wall of  M. tuberculosis , is injected intradermally. Development of a red, slightly swollen, firm lesion at the site of injection after 48–72 hours indicates a positive test. A positive test indicates that the person has been infected with the bacteria but does not confirm the presence of the disease, tuberculosis. However, if a person with a tuberculin-negative skin test becomes positive , then it indicates that the patient has been recently infected. The skin test, however, can even become negative in: Infected persons receiving therapy with immunosuppressive drugs (such as corticosteroids and anticancer drugs) and In those suffering from the diseases associated with suppressed cell-mediated immunity (such as AIDS, sarcoidosis, lymphoma, post measles vaccination, etc.

11.   The response to  M. tuberculosis  illustrates that while on one hand mechanisms involved in DTH are required for defense against the organism; on the other hand, these are also responsible for tissue damage in the longer run. Cytokines (like TNF and IFN- γ ) , which have been produced to activate the macrophages and thus contain the infection, also trigger other cascades that lead finally to extensive tissue damage. Various other skin tests are used to detect DTH. These include many skin tests in bacterial, fungal, viral, and helminthic infections. Lepromin test is a useful test for leprosy . A positive lepromin test indicates the presence of tuberculoid leprosy with intact cell-mediated immunity. On the other hand, a negative lepromin test indicates the presence of lepromatous leprosy with impaired cell-mediated immunity. Positive skin tests in coccidioidomycosis, paracoccidioidomycosis and other fungal infections suggest exposure to the fungi. In both viral and parasitic infections, skin tests are less specific and less useful than the serological tests for diagnosis.

12. Delayed drug reactions Lichenoid drug eruption Morbilliform drug reaction Toxic epidermal necrolysis

13. Treatment Treatment of type IV hypersensitivity depends on the clinical condition that resulted from this reaction. Contact dermatitis: Removing the offending agent is the most crucial aspect of managing this condition. The severity of the skin condition dictates the type of therapy, which would almost always include topical steroids, titrating the strength of the steroid to the severity of the dermatitis. For Steven Johnson syndrome/toxic epidermolysis , aggressive life-saving therapy would be required, including admission to an intensive care unit, optimal fluid therapy, antibiotics if there is a secondary infection, and systemic corticosteroids. For granulomatous conditions, therapy depends on the type of clinical condition. In both systemic and ocular sarcoidosis, steroid therapy is the standard treatment. In addition to steroids, methotrexate has shown efficacy in pulmonary sarcoidosis. In Crohn's disease, anti-tumor necrosis factor (TNF) monoclonal antibodies can be used as an effective way to manage the disease. In schistosomiasis, praziquantel can be used. Once the tuberculin test has revealed a positive result, the treatment of tuberculosis must be started, and one of the commonest regimens is to give rifampin, isoniazid, pyrazinamide, and ethambutol.

14. Type V (Stimulatory Type) Hypersensitivity In this type of hypersensitivity reaction, antibodies combine with antigens on cell surface, which induces cells to proliferate and differentiate and enhances activity of effector cells. It is likely a subset of type II hypersensitivity reactions , as it involves an antibody targeting a specific structure within the body. No dermatological type V hypersensitivity reactions have been described. Type V hypersensitivity reaction plays an important role in pathogenesis of Graves’ disease , in which thyroid hormones are produced in excess quantity . It is postulated that long-acting thyroid-stimulating antibody, which is an autoantibody to thyroid membrane antigen, combines with thyroid-stimulating hormone (TSH) receptors on a thyroid cell surface. Interaction with TSH receptor produces an effect similar to the TSH, resulting in an excess production and secretion of thyroid hormone, which is responsible for Graves’ disease. Another example is Myasthenia Gravis . In this condition, antibodies target acetylcholine receptors at the neuromuscular junction, impairing muscle contraction and causing weakness Graves’ disease

15. References Brainkart - Type III, IV, and V hypersensitivity reactions Usman N, Annamaraju P. Type III Hypersensitivity Reaction. [Updated 2023 May 22]. In: StatPearls Marwa K, Kondamudi NP. Type IV Hypersensitivity Reaction. [Updated 2023 Aug 12]. In: StatPearls DermNet - Allergies explained Hypersensitivity reactions type 3 and 4 - Slideshare

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