111 Immune Disorders – Type IV Hypersensitivity Reactions

Type IV hypersensitivity reactions are characterized by delayed, exaggerated immune responses involving activated antigen-presenting cells (APCs, such as monocytes, macrophages, and dendritic cells) and T lymphocytes. These reactions, sometimes called cell-mediated responses, typically do not involve B lymphocytes. Examples include Allergic Contact Dermatitis, the Mantoux Tuberculin Skin Test, and Delayed/Chronic Transplant Rejections.

1. Allergic Contact Dermatitis
   In this condition, individuals can develop reactions to allergens from substances like poison ivy, latex, soaps, dyes, fragrances, topical medications, or other chemicals, with over 300 known allergens capable of causing this dermatitis. The allergen penetrates the skin, where it is detected and engulfed by APCs. These APCs release cytokines and chemokines that attract and recruit leukocytes, then display the allergen on Class II MHC cell surface molecules, presenting these complexes to CD4+ Helper T lymphocytes (T_H cells).  TH cells with complementary T cell receptors (TCRs) bind to these antigen-bound MHC II complexes, become activated, release cytokines, and proliferate, producing more T_H cells, some of which become Memory T_H cells.  T_H cells also stimulate CD8+ Cytotoxic T cells (T_C cells) to search for and destroy cells displaying the targeted antigen/hapten.  This activation releases cytokines and toxins that damage cells and activate mast cells and basophils, leading to the release of pro-inflammatory cytokines and other toxins.  Clinical manifestations include skin rashes, inflammation, pruritus, blisters, and lesions, typically occurring 48-72 hours after exposure to the allergen.  Treatment usually involves avoiding allergic triggers and using topical corticosteroids.  Memory T_H and T_C cells can lead to repeated clinical manifestations upon subsequent exposure to contact allergens.
2. Tuberculin Skin Test (Mantoux Skin Test)
   The tuberculin skin test determines whether an individual has been infected with Mycobacterium tuberculosis. This is useful in diagnosing current illnesses and assessing past exposure to the bacteria, especially since tuberculosis (TB) is highly infectious and serious, requiring quick treatment to limit its spread. The test leverages the presence of Memory T_H cells from a prior M. tuberculosis infection. It involves an intradermal injection of purified proteins (tuberculin) from the bacteria.  If previously infected, Memory T cells activate and induce an immune reaction, causing a swollen, hard raised area (wheal response) larger than 5mm, which may or may not be red.  As this response takes 1-2 days to develop, the test requires two visits to a healthcare professional: one for the injection and another two days later for measuring any reaction.  A positive test indicates prior or current TB exposure, prompting further tests like sputum culture and lung x-rays to check for active tuberculosis.
3. Delayed Transplant Rejection
   The Type IV hypersensitivity reaction in delayed or chronic transplant rejection involves T_H cell and macrophage-induced cytotoxicity and inflammation, often accompanied by a humoral immune response. Once activated APCs, T_H cells, and T_C cells release cytokines, enzymes, toxins, and chemokines, leading to white blood cell recruitment, inflammation, and progressive destruction of the transplanted organ/tissue. Chronic or delayed allogenic (Host versus Graft) rejection typically starts several weeks to months post-transplantation through four primary mechanisms:

• Direct Pathway: Allogeneic MHC I molecules on cells of the graft are recognized by recipient T_C cells as non-self, which then launch an attack, targeting graft cells for destruction.
• Indirect Pathway: Recipient’s APC MHC II molecules present graft antigens to recipient’s T_H cells, which then stimulate T_C cell activity and B cell production of anti-graft antibodies, both of which targeting graft cells for destruction.
• Non-MHC Antigens: Even with accepted MHC alleles, delayed or chronic rejection can occur when graft cells display cellular peptides (non-MHC antigens) on their MHC molecules recognized by the host’s T_C cells as non-self.
• Missing MHC Antigens:  Additionally, graft cells lacking MHC self-antigens may be targeted by the innate immune system, specifically Natural Killer (NK) cells.

Graft versus Host Rejection involves similar mechanisms, but in this scenario, the activated T, B, and NK lymphocytes belong to the graft (e.g., donated bone marrow), attacking the recipient’s cells.

Summary:

Type IV hypersensitivity reactions are characterized by delayed exaggerated immune responses that involve activated antigen presenting cells (APCs, such as monocytes, macrophages, and dendritic cells) and T lymphocytes.  For this reason, Type IV hypersensitivity reactions are sometimes called cell-mediated responses, typically not involving B lymphocytes (humoral responses).  Three examples of Type IV hypersensitivity reactions include: Allergic Contact Dermatitis, the Mantoux Tuberculin Skin Test, and Delayed/Chronic Transplant Rejections.

1. Allergic Contact Dermatitis

• Scenario: In this case, individuals can develop reactions to allergens from poison ivy, latex, soaps, dyes, fragrances, topical medications, or other chemicals.  There are over 300 allergens known to be possible causes of allergic contact dermatitis.
  • In all cases, the exogenous chemical takes the form of an allergen (antigen or hapten), that penetrates/dissolves into the skin.  Within the epidermis or dermis, the allergen is detected and engulfed by APCs, which become active releasing cytokines and chemokines attracting and recruiting leukocytes (e.g., neutrophils, eosinophils, monocytes).  The APCs display the allergen on Class II MHC cell surface molecules and present these complexes to CD4+ Helper T lymphocytes (T_H cells) that have complimentary T cell receptors (TCRs).  T_H cells that have T cell receptors (TCRs) that are able to bind to these MHC II complexes become activated releasing cytokines and proliferating to produce more T_H cells (some of which will become Memory T_H cells).  T_H cells stimulate CD8+ Cytotoxic T cells (T_C cells) activity which search and destroy all cells that display the targeted antigen/hapten.  The activation of APCs and T lymphocytes in this manner results in the release of cytokines and toxins that damage cells, and activate mast cells and basophils.  Degranulation of mast cells and basophils results in the release of pro-inflammatory cytokines (histamine, bradykinin, prostaglandin and leukotriene) and other toxins.  Clinical manifestations include: skin rashes, inflammation (redness, warmth, swelling), pruritus (itchiness), blisters, and/or lesions.  Symptoms typically occurring 48-72 hours after exposure to triggering allergen.
  • This overreaction of T lymphocytes takes time to develop and is usually treated by prevention (avoiding allergic triggers) and topical corticosteroids.  As both Memory T_H cells and Memory T_C cells are created, subsequent exposure to contact allergens, can readily lead to repeated clinical manifestations.

1. Tuberculin skin test (also known as Mantoux skin test):

Scenario: In this case, the tuberculin skin test is used to determine whether an individual has been infected with M. tuberculosis.  This can be helpful in determining the cause of a current illness within the individual, as this bacterial infection, elicits signs and symptoms that are similar to other pathogen infections.  Determining the exact pathogen is valuable in choosing the most effective treatments.  Additionally, the tuberculin skin test is helpful in determining whether an individual that has been exposed to M. tuberculosis and has a live infection, despite possibly being asymptomatic.  This information is helpful in ensuring that the spread of tuberculosis is limited.  Tuberculosis is highly infectious and spread through contact and respiratory droplets, having serious consequences in most individuals, hence the need to treat quickly and limit the spread especially to vulnerable individuals.  The tuberculin skin test takes advantage of the fact that a live infection with M. tuberculosis will produce Memory T_H cells.  The test involves the intradermal injection of an antigen (purified proteins called tuberculin) from the M. tuberculosis bacterium. If an individual has been previously infected with M. tuberculosis, their Memory T cells will become activated and induce an immune reaction causing the region to become swollen in a hard raised region of more than 5mm, that may or may not be red in appearance.  As it takes 1-2 days for Memory T cells to become active, the tuberculin skin test requires 2 visits to the health care professional.  The initial visit involves the injection and 2 days later, the second visit involves measurement of any palpable hard raised area (wheal response) at the site of the injection.  A positive reaction indicates prior exposure to tuberculosis.  Further tests will be performed to assess for active tuberculosis, that include: sputum culture tests and lung x-rays.

2. Delayed Transplant rejection: The Type IV hypersensitivity reaction mechanism that occurs in delayed/chronic transplant rejection (including both allograft rejection and graft versus host disease) involves T_H cell and macrophage induced cytotoxicity and inflammation.  Additionally, often a humoral immune response is also induced.
   • In the case of chronic or delayed allogenic (Host versus Graft) rejection, the immune response begins several weeks to months post-transplantation and often involves at least four mechanisms including:
     • Direct Pathway: T_C cells recognize allogenic MHC I on transplant as non-self and becomes sensitized and actively induce destruction of allogenic transplant. Summary: Graft MHC I molecules recognized by recipient’s T_C cells as non-self and graft cells targeted for destruction.
     • Indirect Pathway: T_H cells recognize and are stimulated by APCs that are presenting allogenic (graft) antigens displayed by the MHC II molecules. Activated T_H cells proliferate generating T_H cells that enhance T_C cell activity as well as stimulate B cell activity and production of antibodies that target the allogenic transplant for destruction.  Summary:  Recipient’s APC MHC II molecules present graft (non-self) antigens to recipient’s T_H cells, which stimulate T_C cell activity and B cell production of anti-graft antibodies and graft cells targeted for destruction.
     • Activated APCs, T_H cells and T_C cells all release cytokines and chemokines which lead to WBC recruitment, inflammation and progressive destruction of transplanted/graft organ/tissue.
     • Rejection may be asymptomatic for delayed until significant damage to the transplant organ has occurred. This could be weeks, months, or years after T cell and B cell mediated destruction has started.
     • Non-MHC Antigens: When the MHC alleles of the graft are not targeted for destruction, there is more chance of a prolonged acceptance of the graft or even a completely successful transplant.  However, even when MHC alleles are accepted by the recipient’s immune system, a delayed or chronic rejection may still occur.  This is thought to happen when the graft cells display cellular peptides (non-MHC antigens) on their MHC molecules that are recognized by the host’s TC cells as non-self, triggering the launch of a cell-mediate immune response directed against the graft.
     • Missing MHC Antigens: Graft/transplant cells that lack MHC self-antigens may be targeted by the innate immune system for destruction, specifically by Natural Killer cells (NK cells also known as NK lymphocytes).
   • Graft versus Host Rejection – involve the same four mechanisms, though in this case the activated T, B, and NK lymphocytes all belong to the graft (e.g., donated bone marrow), and it is the recipient’s cells that are under attack.