Introduction/Definitions:
Hypersensitive reactions are inflammatory reactions within the humoral (Types I-III) or cell-mediated branches of the immune system that lead to extensive tissue damage. Inflammation is a complex process, accompanied by the release of mediators, which, by chemotaxix, attract luekocytes to the point of invasion, create local pain and raise body temperature.
Autograft: tissue transplanted from one site on an individual’s body to another site
Isograft: tissue from an identical twin is used
Allograft: exchanges between genetically different individuals belonging to the same species; the most common types of grafts.
FcεRI: High affinity IgE receptor located on mast cells and other cells such as basophils.
Xenograft: a tissue exchange between individuals of a different species.
Note that some diseases such as Rheumatoid arthritis and ankylosing spondylitis are Type II, III & IV hypersensitivities because they are characterized by vasculitis; frequent target is joint lining; antibodies against other antibodies (rheumatoid factor) and T-cell cytokine damage.
IgE-Mediated (Type I) Hypersensitivity:
Pathology: Allergic diseases such as asthma result from Th2-type immune responses against otherwise harmless environmental antigens. Such responses lead to the generation of Th2 T cells, which produce IL-4 and IL-5 and promote the differentiation of B cells into IgE secreting cells.
This IgE binds to Fc receptors on the membranes of blood and tissue. Cross linkage of the receptor bound IgE molecules by subsequent exposure to induces degranulation of and releasing various granules (histamine) that give rise to allergic manifestations. These molecules cause blood vessels to dilate and become leaky, which in turn helps white blood cells, antibodies and to enter sites of infection. The high-affinity receptor for IgE (Fc?RI) is the key molecule in the triggering of IGE-mediated allergic reaction. Mutlivalent allergens bridge the receptor-bound IgE and induce the aggregation of this receptor on the surface of mast cells and basophils, and trigger the subsequent release of mediators such as histamine that are responsible for allergic symptoms. Interfering with the binding of IgE to this receptor is considered to be a strategy for the specific prevention of the IgE mediated allergic reaction. For example, recombinant and synthetic peptides comprising structural elements of human IgE or human FcεRI have been investigated as competitive inhibitors for the IgE-FcεR Iinteraction. Searches have also been made for monoclonal antibodies against IgE or FcεRI(the extracellular portion). Takai (Japanese Bioch. Society, 129(1), 2001) report that a Fab fragment of a humainzed antibody against the membrane proximinal IgE-binding domain of human FcεRI inhibits the release of histamine from human basophils. Interesting this same article reports that secretion of Fabs without the Fc gene was remarkably enhanced compared to that when transfected with the Fc gene.
Clinical manifestations of type I reactions include hay fever and asthma.
People with allergic disorders such as atopic dermatitis (eczema), allergic rhinitis (hay
fever), food allergy and allergic (or atopic) asthma can experience acute signs and symptoms
of disease within minutes of exposure to the associated allergens. However, such individuals
also typically develop long-term changes in the affected tissues, often called tissue
remodeling, after repeated exposure to these allergens over periods of weeks to years. There
is consensus that antigen-specific IgE antibodies, together with one of the major effector
cells of allergy, the mast cell, can be crucial for the development of the acute
manifestations of these allergic disorders. (Tsai “IgE and mast cells in allergic disease” Nature Medicine, 8, pages693–704 (2012))
Once an individual has developed IgE antibodies to certain antigen epitopes, multiple
mechanisms can lead to a more robust and diverse IgE responses to both the original as well
as other antigens. Some of these mechanisms are mediated by CD23, which can be
expressed on cells such as epithelial cells, B cells and myeloid cells. CD23 is a Ctype lectin that can exist in a membrane-bound form that has three lectin domain “heads”
separated from the membrane by a triple α-helix coiled-coil stalk, as well as in various
soluble forms whose functions depend on whether these soluble forms are monomeric or
trimeric. CD23 is thought to contribute to both positive and negative regulation of IgE production, but the mechanisms responsible for this, and the role of CD23 in the pathology of
allergic diseases, are not fully understood. (Tsai “IgE and mast cells in allergic disease” Nature Medicine, 8, pages693–704 (2012))
IgE does not fix complement and has only limited ability to cross the placenta, and it is
thought that IgE’s main biological roles reflect its ability to bind to receptors on mast cells,
basophils and a variety of other cell types. The high-affinity receptor for IgE, FcεRI, as
expressed by mast cells and basophils, consists of an IgE-binding α chain, in which the two
extracellular domains bind IgE, a β chain, which spans the plasma membrane four times and
functions as a signal amplifier, and two identical and largely intracellular γ chains. (Tsai “IgE and mast cells in allergic disease” Nature Medicine, 8, pages693–704 (2012))
In an allergic person, whose tissue mast cells and other cell types already have antigenspecific IgE bound to FcεRI, re-exposure to the original or a crossreactive bivalent or
multivalent antigen results in the crosslinking of adjacent FcεRI-bound IgE and the
consequent aggregation of surface FcεRI. When the FcεRI aggregation is of sufficient
strength and duration, it triggers mast cells and basophils to initiate complex signaling
events that ultimately result in the secretion of a diverse group of biologically active
products. Tsai “IgE and mast cells in allergic disease” Nature Medicine, 8, pages693–704 (2012))
Some products, such as those stored preformed in the cells’ cytoplasmic granules, for example, histamine, serotonin (in rodents to a much greater extent than in humans), proteases such as tryptase, chymase and/or carboxypeptidase A3 and proteoglycans (heparin and/or chondroitin sulfates), as well as newly formed lipid-derived mediators, for example, PGD2, LTB4, LTC4, LTD4 and LTE4 and certain cytokines, are released by mast cells within minutes of antigen exposure. Others, including a diverse spectrum of cytokines, chemokines and growth factors, are produced in mast cells from new transcripts and are therefore secreted over a period of hours after the initial mast cell activation. Studies in mice suggest that, in addition to IgE, immunoglobulin light chains can also mediate antigen-specific mast cell activation, although the receptor responsible for this effect has been elusive. Tsai “IgE and mast cells in allergic disease” Nature Medicine, 8, pages693–704 (2012))
In aggregate, mediators released shortly after antigen- and IgE-induced mast cell
degranulation induce a response termed an immediate hypersensitivity (or early phase)
reaction within minutes of their release. If localized to the airways, this response is
characterized by increased vascular permeability, contraction of the airway smooth muscle
and enhanced secretion of mucus, resulting in acutely reduced airflow and wheezing. If the response is systemic, it can result in anaphylaxis, a catastrophic immune response that can rapidly result in death if not properly treated. Tsai “IgE and mast cells in allergic disease” Nature Medicine, 8, pages693–704 (2012))
Hay Fever (allergic rhinitis): is due to seasonal reaction to inhaled plant pollen or molds, or a chronic, year-round reaction to airborne allergens or inhalants.
Asthma: is a Respiratory disease characterized by episodes of impaired breathing due to severe bronchoconstriction. Symptoms range from bouts of difficult breathing to fatal suffocation.
Atopic Dermatitis/Eczema: (see also skin care)
Eczema results in intensely itchy inflammatory condition of the skin. It usually begins in infancy and is characterized by reddened, encrusted skin lesions on the face, scalp, neck, and inner surfaces of limbs and trunk. It progresses to a dry, scaly, thickened skin condition in adults.
Food and Drug allergy:
Food allergy hypersensitivity involves IgE and degranulation of mast cells, but not all reactions involve this mechanism.
Anaphylaxis: is an Overpowering IgE-Mediated Allergic Reaction. Bee stings and injection of antibiotics or serum are most commonly implicated.
Diagnosis:
–Radioallergosorbent (RAST) test: measures levels of IgE to specific antigens.
–Tryptase test: measures tryptase, an enzyme released by mast cells that increases during an allergic response.
–Differential blood cell count can reveal high levels of basophils and eosinophils.
–Leukocyte histamine-release test: measures the amount of histamine released from the patient’s basophils when exposed to a specific allergen.
–Skin testing: in vivo method to detect precise atopic or anaphylactic sensitivities.
Treatment:
–Introduction: Therapeutic approaches in allergic diseases have for many years included attempts to target particular mediators that can be derived from mast cells and, in many cases, also from other cells types. In addition, corticosteroids, whose effects can suppress many
proinflammatory pathways, including some that may depend on mast cell functions such
as cytokine production, can ameliorate disease in many individuals with asthma and other allergic disorders. However, although such approaches have been useful in many patients, there are major unmet therapeutic needs, particularly in asthma.
–Anti-IgE antibodies: Given their role as key drivers of the pathology in allergic disorders, efforts are underway to target IgE and mast cells. Years of clinical experience with omalizumab, a humanized monoclonal antibody to IgE, have shown that it can provide benefit in some patients with moderate to severe asthma. Efforts also are underway to interfere with the binding of IgE to FcεRI. Such work includes the design of small peptides that can block this binding.
—Block the action of lymphocytes, mast cells, or chemical mediators: Almost all current therapeutic efforts against allergic disease have been aimed at the control of the symptoms triggered by mast cell or basophil degranulation.
Treatments typically block the action of lymphocytes, mast cells, or chemical mediators.
—Skew Immune Response away from TH2 Response: a more fundamental approach to disease therapy might be to prevent the initial generation of the Th2 like immune response against the allergen, or to induce a Th1 like response against the allergen since Th1 and Th2 immune responses are typically mutually inhibitory.
–Desensitization: controlled exposure to the antigen through ingestion, sublingual absorption, or injection to reset the allergic reaction has sometimes been used.
Antibody-Mediated Cytotoxic (Type II) Hypersensitivity (Reactions that Lyse Foreign Cells):
Type II hypersensitivity reactions involve antibody-mediated destruction of cells. Antibody can activate the creating pores in the membrane of a foreign cell, or it can mediate cell destruction by . Antibody bound to a foreign cell can also serve as an opsonin, enabling phagocytic cells with Cc or C3b receptors to bind and phagocytose the antibody-coated cell.
Type II hypersensitivities are a complex group of syndromes that involve complement-assisted destruction (lysis) of cells by antibodies (IgG and IgM) directed against those cells’ surface antigens.
Rh Incompatability: occurs when a motherʼs immune system detects the foreign Rh factors on fetal RBCs and is sensitized to them by producing antibodies and memory B cells
Transfusion reactions are Type II Reactions. For example, if a type A person is transfused with blood containing type B cells, anti-B iso-hemagglutinins bind to the B blood cells and mediate their destruction by means of complement mediated lysis.
Autoimmne diseases (Inappropriate response to self):
–Myasthenia gravis: See autoimmune disorders
Antibodies against the acetylcholine receptors on the nerve-muscle junction alter function
–Graves’ Disease:
Antibodies against thyroid-stimulating hormone receptors
–Multiple Sclerosis: (also type III hypersensitivity)
T cells and antibodies sensitized to myelin sheath destroy neurons.
Immune Complex Mediated (Type III) Hypersensitivity (Immune Complex Reactions):
Introduction: The reaction of antibody with antigen generates immune complexes which usually facilitates the clearance of antigen by phagocytic cells. In some cases, however, large amounts of immune complexes lead to tissue damaging type III hypersensitive reactions. Much of the tissue damage in type III reactions occurs from release of lytic enzymes by neutrophils as they attempt to phagocytose immune complexes. See Annamaraju
Antigen–antibody immune complexes that circulate in the blood and deposit in tissues, where they activate complement, recruit neutrophils and macrophages, and trigger inflammation and tissue injury underlie type III hypersensitivity. Unlike type II hypersensitivity, where antibodies target fixed cell-surface antigens, type III reactions involve soluble antigens forming circulating immune complexes that preferentially accumulate in filtration-rich organs such as the kidneys, joints, blood vessels, and lungs. The resulting pathology manifests as conditions such as serum sickness, PSGN, SLE, rheumatoid arthritis, hypersensitivity pneumonitis, IgA nephropathy, IgA vasculitis, PAN, and localized Arthus reactions. Annamaraju
Type III hypersensitivity reactions occur when the immune system forms clusters of antibodies and antigens, called immune complexes, that circulate in the blood and deposit in tissues such as the kidneys, joints, skin, or lungs. Instead of protecting the body, these complexes trigger inflammation that can cause fever, rashes, joint pain, kidney problems, pulmonary issues, or vasculitis. In simpler terms, the immune system “overshoots,” and the cleanup process designed to protect the body ends up irritating and damaging healthy tissues. Annamaraju
Type III hypersensitivity reactions occur when antigen–antibody complexes form in the circulation and are not adequately cleared, leading to tissue deposition. These immune complexes activate the classical complement pathway, producing chemotactic factors that recruit neutrophils and other inflammatory cells. The resulting release of proteolytic enzymes and reactive oxygen species causes local inflammation and tissue injury. Clinical manifestations vary by site of deposition and may include arthritis, vasculitis, glomerulonephritis, or systemic syndromes such as serum sickness. Disorders such as systemic lupus erythematosus, post-streptococcal glomerulonephritis, and specific drug- or infection-related conditions exemplify the broad spectrum of immune complex–mediated diseases. Annamaraju
Acute post-streptococcal glomerulonephritis (APSGN): occurs when particular types of Group A Step cause disease, such as sore throat or skin infection. Antibody/streptococcal antigen complexes settle into the basement membranes of the kidney. Complement activation leads to infiltration of neutrophils and kidney damage occurs. Annamaraju
Rheumatoid Arthritis: Rheumatoid arthritis (RA) is primarily a Type III hypersensitivity, but it also has Type IV features.
Post-Streptococcal Glomerulonephritis:
–Diagnosis: Clinical findings of acute nephritis, marked by hematuria with or without RBC casts, proteinuria, edema, oliguria, and hypertension, and documentation of a recent group A ß-hemolytic streptococcal infection typically establish the diagnosis of PSGN. Throat cultures have limited utility, with positivity in only 10% to 20% of patients. In 94.6% of cases, elevated streptococcal antibody titers such as anti-streptolysin O, anti-streptokinase, and anti-DNase B are present. Annamaraju
–Treatment: Patients with PSGN and the presence of an ongoing streptococcal infection should receive penicillin or erythromycin if penicillin allergic. The remainder of care is supportive, focusing on treating the complications. Sodium and water restriction, as well as loop diuretics, treat volume overload, pulmonary edema, and hypertension. In the event hypertensive encephalopathy develops, clinicians use oral nifedipine or IV nicardipine. Severe renal impairment manifesting as uremia, defined as a BUN between 89 and 100 mg/dL, volume overload unresponsive to therapy, or a serum or plasma potassium greater than 6.5 mEq/L, unresponsive to medical therapy, warrants dialysis. Annamaraju
Systemic lupus erythematosus (SLE): involves inflammation of many organs; antibodies against red and white blood cells, platelets, clotting factors, nucleus DNA.
–Diagnosis:The evaluation of SLE involves a combination of laboratory and imaging studies to assess systemic involvement and guide management. The CBC may reveal hematologic abnormalities such as leukopenia, neutropenia, and thrombocytopenia. At the same time, an elevated creatinine, abnormal urinalysis with hematuria, pyuria, proteinuria, or casts, and a high urine protein-to-creatinine ratio suggest renal involvement. Elevated creatine kinase may indicate myositis, and hypergammaglobulinemia on serum protein electrophoresis reflects systemic inflammation. Serologic testing is central: ANA is almost always positive during the disease course; anti-dsDNA antibodies are present in about 70% of cases; and anti-Sm, anti-RNP, anti-Ro/SSA, and anti-La/SSB antibodies occur with varying frequencies and overlap with other connective tissue diseases. Titers of anti-dsDNA antibodies vary with disease activity, making them good indicators of disease activity and treatment response. Annamaraju
–Treatment: SLE requires a tailored, multi-agent approach. Patients should understand the importance of photoprotection and avoid smoking, as it increases the risk of active disease. They should also receive necessary immunizations before starting immunosuppressive medications and undergo routine monitoring of vitamin D levels, considering the need for sun avoidance. All patients benefit from hydroxychloroquine for disease control and reduction of flares. dditionally, NSAIDs and a short course of glucocorticoids may be necessary in patients with mild disease. Those with moderate disease may require a longer course of glucocorticoids until the full effect of hydroxychloroquine is evident. Patients with severe, organ-threatening disease often require a short course of high-dose glucocorticoids in combination with mycophenolate, cyclophosphamide, or rituximab. Annamaraju
Serum Sickness:
–Diagnosis: In serum sickness, a CBC may reveal neutropenia, eosinophilia, or thrombocytopenia. Elevated ESR and CRP levels are common, reflecting systemic inflammation—complement consumption results in low serum C3, C4, and CH50. Urinalysis may reveal mild proteinuria, and skin biopsies typically show leukocytoclastic vasculitis. Diagnosis primarily depends on the temporal relationship between antigen exposure and the classical triad of fever, rash, and arthritis, rather than a single confirmatory test. Annamaraju
–Treatment: Antihistamines and NSAIDs provide symptomatic relief of mild systemic symptoms such as arthralgia, rash, or low-grade fever associated with serum sickness. In moderate to severe cases, systemic corticosteroids are helpful to reduce immune-complex–driven inflammation. While patients should avoid reexposure to the offending agent, premedication with antihistamines and steroids may also prevent recurrence if reexposure is necessary in the future. Annamaraju
Secondary Polyarteritis Nodosa:
–Diagnosis: The diagnosis of PAN is clinical. Laboratory evaluation helps determine the extent of organ involvement and investigate the differential diagnoses. Initial laboratory tests include a CBC, serum creatinine, muscle enzyme concentrations, liver function studies, hepatitis B and C serologies, and a urinalysis. A chest radiograph helps exclude other vasculitides that primarily affect the lungs. Blood cultures are necessary to exclude endovascular infection. Additional potential testing depends on patient presentation and potential differential diagnoses. Possible tests include antineutrophil cytoplasmic antibodies, antinuclear antibodies, C3 and C4, cryoglobulins, serum and urine electrophoresis, HIV testing, testing for adenosine deaminase 2 deficiency, and VEXAS syndrome. A positive antineutrophil cytoplasmic antibody suggests ANCA-associated vasculitides, whereas a positive ANA suggests underlying SLE or systemic sclerosis. Ideally, a biopsy of the affected organ, revealing inflammation of the medium-sized arteries, should confirm the diagnosis. Annamaraju
–Treatment: Patients with hepatitis associated PAN should receive treatment with antivirals as initial treatment. Patients with severe or persistent disease may require systemic glucocorticoids or an immunosuppressant medication; however, clinicians should monitor the status of the underlying infection. Clinicians can use plasma exchange as an alternative for patients with progressive disease who cannot receive immunosuppressive therapy. If an immunosuppressant is necessary, first-line choices are azathioprine or methotrexate. Annamaraju
Type IV Hypersensitivities: Cell-Mediated (Delayed) Reactions:
Type IV hypersensitivities involves primarily the T-cell branch of the immune system. It results when T cells respond to antigens displayed on self tissues or transplanted foreign cells. It is traditionally known as delayed hypersensitivity because symptoms arise one to several days following the second contact with antigen.
Contact Dermatitis: is caused by exposure to resins in poison ivy and poison oak, haptens in household and personal articles, and certain drugs. It requires a sensitizing dose followed by a provocative dose.
Allergen penetrates the outer skin layers which are processed by skin dendritic cells and presented to T cells, subsequent exposures attract lymphocytes and macrophages and c ells release enzymes and cytokines that damage the epidermis in the immediate vicinity. Contact dermatitis occurs when contact allergens penetrate the skin’s stratum corneum and bind to skin proteins, forming hapten-protein complexes. Langerhans cells engulf the hapten complex and present it to T cells in the lymph nodes. Following the initial exposure, the patient develops hapten-specific memory T cells, which undergo clonal expansion and circulate throughout the body until recruited to the skin upon reexposure to the offending antigen. Following initial hapten exposure, Langerhans cells mature and express CD83, adhesion molecules (such as intercellular adhesion molecule-1 [ICAM-1]), and stimulatory molecules (including CD40, CD80, and CD86). Upon reexposure to the same antigen, the antigen-presenting cells present the hapten complex to memory T cells in the dermis and epidermis. See Kondamudi
The initial damage primarily results from major histocompatibility complex (MHC) class I CD8+ T cells infiltrating the skin and inducing keratinocyte apoptosis via the perforin/granzyme or Fas/FasL pathway. This leads to intercellular edema and vesiculation due to the cleavage of intracellular adhesion molecules and lymphocyte infiltration into the epidermis. Infiltrating CD8+ T cells release cytokines such as IFN-γ and TNF-α, which stimulate keratinocytes, resulting in the upregulation of ICAM-1 and MHC class II molecules. This cascade recruits neutrophils, macrophages, and eosinophils, causing skin inflammation, swelling, itchiness, and pain. The precise role of CD4+ T cells remains unclear, as they appear later in the reaction than CD8+ T cells. These CD4+ T cells also secrete large amounts of IFN-γ and TNF-α and may contribute to cytotoxicity against cells expressing MHC II, act as mediators of the inflammatory response, or serve a regulatory function. See Kondamudi
Tuberculosis Infection: Diagnosis includes a tuberculin reaction
Transplantation or grafting of organs and tissues (Host versus Graft Rejection): is a common medical procedure, but it is plagued with the natural tendency of lymphocytes to seek out and destroy foreign antigens.
When a donor tissue (graft) displays surface molecules of a different MHC class, the T cells of the recipient will react to it as a foreign substance. Cytotoxic T cells of a host recognize foreign class I MHC markers on the surface of grafted cells. Helper and cytotoxic T cells bind to the grafted tissue and secrete lymphokines that begin the rejection process within 2 weeks of transplantation. Antibodies formed against the transplanted tissue contribute to damage.
Graft versus host disease (GVHD) (Graft Rejection of Host):
Some grafted tissues (bone marrow) contain indigenous populations of passenger lymphocytes
These lymphocytes make it quite possible for the graft to reject the host
Autoimmune Diseases:
–Type I Diabetes:
T cells attack insulin-producing cells.
–Multiple Sclerosis: (also type II hypersensitivity)
T cells and antibodies sensitized to myelin sheath destroy neurons.