Hypersensitivity

Reactions Type 3
and Type 4

Salome Sibashvili
Type 3 Hypersensitivity Reaction

– Type III hypersensitivity reactions, also referred to as immune complex reactions,

are antibody-mediated.
– The amount of immune complex deposition in tissues is determined by the nature
of the complexes and the characteristics of the blood vessels.
– Antigen-antibody complexes are produced during normal immune responses are
not efficiently cleared, and become deposited in tissues.
– Small complexes are often not phagocytosed and tend to be deposited in vessels
more than large complexes, which are usually cleared by phagocytes. Complexes
containing cationic antigens bind avidly to negatively charged components of the
basement membranes of blood vessels and kidney glomeruli
 Pathophysiology
– Immune complexes deposited in vessel walls and tissues activate leukocytes and
mast cells to secrete cytokines and vasoactive mediators.
– These mediators may cause more immune complex deposition in vessel walls by
increasing vascular permeability and blood flow.
– The major mechanism of tissue injury in immune complex diseases is inflammation
within the walls of blood vessels, resulting from complement activation and
binding of leukocyte Fc receptors to the antibodies in the deposited complexes.
– Antigen (e.g., the molecules of a drug in circulation) binds to IgG to form an
immune complex (antigen-antibody complex)
– Immune complexes are deposited in tissue, especially blood vessels → initiation of
complement cascade → release of lysosomal enzymes from neutrophils → cell
death → inflammation → vasculitis
– Many systemic immunologic diseases in humans are caused by the deposition of
immune complexes in blood vessels.
Arthus Reation
– A local subacute type III hypersensitivity reaction.
– Typically caused by vaccination against tetanus and/or diphtheria.
– Circulating antibodies rapidly bind to the injected antigen and form immune
complexes that are deposited in the walls of small blood vessels at the injection
site.
– This deposition gives rise to a local cutaneous vasculitis, with thrombosis of the
affected vessels, leading to tissue necrosis.
– Cutaneous small-vessel vasculitis
– Localized swelling, erythema, hemorrhage
– Occasional superficial skin necrosis a few hours after booster vaccination
– The reaction typically peaks after 12–36 hours.
– The reaction is self-limited.
– Symptomatic relief of swelling (e.g., cold compresses, NSAIDs, limb elevation)
Serum Sickness
– The prototypic immune complex disease.
– Serum sickness is a classic example of a type III hypersensitivity reaction, which
usually develops as a complication of antitoxin or antivenom administration.
– Antibodies to foreign proteins are produced and 1–2 weeks later, antibody
antigen complexes form and deposit in tissues complement activation
inflammation and tissue damage.
– Fever, urticarial , arthralgia, proteinuria, lymphadenopathy occur 1–2 weeks
after antigen exposure.
– Serum sickness-like reactions are associated with some drugs (may act as
haptens , eg , penicillin) and infections (eg, hepatitis B).
Type IV Hypersensitivity Reaction

– Type IV hypersensitivity reactions are delayed and cell-mediated.

– Compared to type I-III hypersensitivity reactions, which are antibody-mediated, type IV
reactions are mediated by T cells. Type IV hypersensitivity reactions involve two major steps:
– T cell sensitization: skin penetration by the antigen → uptake of the antigen by Langerhans cell
→ migration to lymph nodes → formation of sensitized T lymphocytes
– Presensitized T cell response (after repeated contact with the antigen)
– CD4+ T cells recognize antigens on antigen-presenting cells → release of inflammatory
lymphokines cytokines (e.g., IFNγ, TNF α) → macrophages activation → phagocytosis of target
cells
– CD8+ T cells recognize antigens on somatic cells → cell-mediated cytotoxicity → direct cell
destruction
CD4- – Type IV hypersensitivity reactions are mediated by antigen-specific T cells, unlike all
other hypersensitivity reactions, which are antibody-mediated. T helper cells (CD4+
mediated cells; Th cells) mainly act by cytokine-mediated recruitment of inflammatory cells to
the site of the target cells.
type IV – T-cell receptors (TCR) present on sensitized CD4+ cells recognize and bind to specific
hypersensi exogenous antigens (e.g., bacteria, viruses). These antigens are bound to the major
histocompatibility complex class II (MHC II), a transmembrane protein present on the
tivity surface of antigen-presenting cells, like macrophages. Th cells are divided into two
subsets based on the cytokines they produce:
reaction – - Bacterial and viral infections predominantly activate Th1 cells, which release
cytokines that preferentially recruit neutrophils and macrophages (e.g., IFNγ, TNFα).
Activated macrophages release reactive oxygen species (ROS) and nitric oxide (NO),
which aid in the destruction of phagocytosed pathogens.
– - Helminthic or parasitic infections predominantly activate Th2 cells, which release
cytokines that preferentially recruit eosinophils (e.g., IL5). Activated eosinophils
release major basic protein (MBP), which aids in the destruction of helminths and
signals mast cells to release histamine.
– Cytokines, ROS, and MBP recruit more inflammatory cells to the site of the reaction
and amplify the inflammatory response, which typically becomes evident ∼ 48 hours
CD8-mediated type IV hypersensitivity
reaction
– Type IV hypersensitivity reactions are mediated by antigen-specific T cells, unlike all other
hypersensitivity reactions, which are antibody-mediated. The cytotoxic T cells ( CD8+ T cell)
mainly act by inducing apoptosis of the target cell.
– T-cell receptors (TCR) located on sensitized CD8+ T cells recognize and bind to
endogenously synthesized antigens (typically viral antigens) that are bound to the major
histocompatibility complex class I (MHC I), a transmembrane protein present on the surface
of nucleated cells and platelets. CD8+ T cells binding to the antigen stimulates two signaling
pathways. These pathways result in apoptosis of the infected cell by activating the
intracellular caspase enzymes and destroying intracellular pathogens in the process.
– - Intrinsic pathway (main pathway): CD8+ T cells release protease granules (granzyme,
perforin) into the infected cell and induce apoptosis.
– - Extrinsic pathway: Fas ligand (FASL) present on CD8+ T cells bind to Fas receptors on the
target cells and induce apoptosis.
– Cytokine pathway: Activated CD8+ T cells also release cytokines that decrease viral
replication and increase the expression of MHC I to amplify the detection of antigens.
Cytokines also recruit macrophages to the site of the reaction, inducing an inflammatory
reaction that typically becomes evident ∼ 48 hours after antigen-exposure (i.e., delayed
Delayed-Type Hypersensitivity
(DTH)
– DTH is an injurious cytokine-mediated inflammatory reaction resulting from the activation
of T cells, particularly CD4+ T cells.
– The reaction is called delayed because it typically develops 24 to 48 hours after antigen
challenge in a previously immunized (sensitized) individual, in contrast to immediate
hypersensitivity (allergic) reactions, which develop within minutes
– Humans may be sensitized for DTH reactions by microbial infection, by contact
sensitization with chemicals and environmental antigens, or by intradermal or
subcutaneous injection of protein antigens .
– Subsequent exposure to the same antigen (called challenge) elicits the reaction. For
example, purified protein derivative (PPD), a protein antigen of Mycobacterium
tuberculosis, elicits a DTH reaction, called the tuberculin reaction, when it is injected into
individuals who have been exposed to M. tuberculosis. A positive tuberculin skin test
response is a widely used clinical indicator of previous or active tuberculosis infection.
– The characteristic response of DTH evolves over 24 to 48 hours.
– About 4 hours after the injection of an antigen in a sensitized individual,
neutrophils accumulate around the postcapillary venules at the injection site.
– By about 12 hours, the injection site becomes infiltrated by T cells and blood
monocytes, also organized in a perivenular distribution . The endothelial cells
lining these venules become enlarged and show increased biosynthetic
organelles, and the vessels leak plasma macromolecules.
– Fibrinogen escapes from the blood vessels into the surrounding tissues, where
it is converted into fibrin. The deposition of fibrin, edema, and the accumulation
of T cells and monocytes within the extravascular tissue space around the
injection site cause the tissue to swell and become firm (indurated).
– Induration, a diagnostic feature of DTH, is detectable by about 18 hours after
the injection of antigen and is maximal by 24 to 48 hours.
Pathogenesis of Autoimmunity
– The key factor in the development of autoimmunity is the recognition of self-
antigens by autoreactive lymphocytes, which then become activated,
proliferate, and differentiate to produce effector cells and cytokines that cause
tissue injury.
– Autoimmunity must initially result from a failure of mechanisms of central
tolerance, as cells are “educated” in the bone marrow and thymus.
– Self-reactive lymphocytes that escaped central tolerance are subject to the
different mechanisms of peripheral tolerance.
– The 3 primary mechanisms that induce peripheral tolerance are anergy,
deletion and suppression.
– Anergy: a lack of a normal immune response to particular antigens, cytokines,
and allergens, usually due to the absence of costimulatory signals
– Deletion of autoreactive T cells through apoptosis
– Suppression: blocking activation by inducing regulatory T cells through exposure
to TGF-β in peripheral tissues
– B lymphocytes that recognize self-antigen in the absence of the T-cell signaling become
anergic and express high levels of IgD on their surface, excluding them from secondary
lymphoid tissues.
– Anergic B lymphocytes are then unable to receive the signals necessary for survival and
undergo apoptosis.
– Additionally, B lymphocytes have inhibitory receptors that can be engaged when self-
antigen is recognized suppressing their activity.
– Similar to self-reactive B lymphocytes, T lymphocytes that recognize self-antigen in the
absence of the appropriate costimulatory signals are subject to anergy or deletion.
– Anergy is the result of a breakdown in either TCR signaling or the binding of an inhibitory
receptor, CTLA-4 or PD-1.
– Deletion of self-reactive T lymphocytes is due to apoptosis by activation of the caspase
signaling pathway or the Fas signaling pathway.
– Self-reactive T lymphocytes are also subject to suppression by Tregs. Although a majority
of Tregs are generated during central tolerance, some arise in the periphery.
– Tregs secrete IL-10 and TGF-beta that inhibit the activation of lymphocytes, macrophage
and dendritic cells. CTLA-4 is expressed at high levels on Tregs and is thought to bind to
and sequester the costimulatory molecule B7 which would otherwise be used to activate
T lymphocytes.
– Development of autoimmune disease is due to a combination of genetic and
environmental factors as well as hormonal triggers. Among the strongest
genetic associations with the development of autoimmune disease are the HLA
genes.
– Also known to contribute to autoimmunity are polymorphisms in non-HLA
genes.
– Infections and tissue injury may alter the way that self-antigens are presented
to lymphocytes and serve as an inciting factor in the development of disease
– Because autoimmune reactions against one self-antigen may injure other
tissues and expose other potential self-antigens for recognition, autoimmune
diseases tend to be chronic and progressive.
– Autoimmunity refers to an immune reaction against the body's own cells that
occurs as a result of a loss of immune tolerance. Women have a
disproportionately higher incidence of autoimmune diseases than men.
Presumed pathogenesis
– Autoreactive B cells are physiologically eliminated in the bone marrow, spleen,
and lymph nodes.
– T cells that attack the body's own cells undergo negative selection in the thymus
or undergo apoptosis in peripheral lymphoid tissues (e.g, lymph nodes,
adenoids, Peyer's patches) due to a lack of stimulation.
– If the selection mechanisms fail, immune cells can attack the body's own cells,
which leads to autoimmune inflammation.
Consequences
– The presence of autoreactive B cells results in the production of irregular
antibodies, which can trigger various diseases.
– Autoantibodies can also be used as a diagnostic tool (see the table below).
– In T-cell mediated autoimmune reactions, there are usually no detectable
specific antibodies (e.g., in multiple sclerosis).
Causes of autoimmune conditions
– Mostly idiopathic
– Sometimes elicited by a previous infection (e.g., Guillain-Barre syndrome, rheumatic fever).
– The underlying pathomechanism is molecular mimicry (the antigenic resemblance between
molecules on some pathogens and those of normal cells in the body)
– Persistent antigenic stimuli
– Breach of central tolerance
– Genetic predisposition, e.g.:
– HLA-B8, e.g., myasthenia gravis, Graves disease, Addison disease
– HLA‑B27, e.g., ankylosing spondylitis, reactive arthritis, psoriatic arthritis, ulcerative colitis
– HLA-DR4, e.g., rheumatoid arthritis, type 1 diabetes, pemphigus vulgaris, Addison disease
– HLA-DR3, e.g., type 1 diabetes, SLE, Hashimoto thyroiditis, Graves disease
– HLA-DR2, e.g., SLE, Goodpasture syndrome, multiple sclerosis
– HLA‑DQ2 and HLA-DQ8, e.g., gluten‑sensitive enteropathy
– HLA-DR5, e.g., Hashimoto thyroiditis
– HLA-A3, e.g., hemochromatosis
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