| What is type IV HS? | ➢ Unlike the other types, it is not antibody mediated but
rather is a type of cell-mediated response.
➢ Type IV HS (DTH) represents immune reactivity where T
lymphocytes have had prior encounter with antigen; it is
mediated by antigen-specific effector T cells and
monocytes/macrophages rather than by antibodies
➢ This reaction is caused when CD4+ Th1 helper T cells recognize foreign antigen in a complex with the MHC class II on the surface of antigen-presenting cells.
➢ These can be macrophages that secrete IL-12, which
stimulates the proliferation of further CD4+ Th1 cells
➢ CD4+ T cells secrete IL-2 and interferon gamma (IFN-γ),
inducing the further release of other Th1 cytokines, thus
mediating the immune response
➢ Another possibility is that if APC presents Ag along with MHCI, then CD8+ cells are stimul |
| How is mechanism of Type IV HS? | Activated CD8+ T cells destroy target cells on contact, whereas activated macrophages produce hydrolytic enzymes and, on presentation with certain intracellular pathogens, transform into multinucleated giant cells
➢ The DTH reaction involves cellular activation of T helper
cells (CD4+) and/or cytotoxic T cells (CD8+CTLs).
➢ Subsequent cytokine secretion gives rise to distinct
pathologies
➢ It is termed ‘delayed‐type’ HS because the reaction usually manifests 12–24 h (two to three days) post antigen exposure.
➢ Type IV reactions not only develop slowly but, depending on whether the antigen persists or is removed, they can be prolonged or relatively transient |
| What are different causes of Type IV HS? | 1. Bacterial causes are Mycobacterium tuberculosis, Brucellosis,
Leprosy, and Syphilis.
2. Viral causes are Smallpox, Measles, Herpes simplex.
3. The fungal cause is Candidiasis, Histoplasmosis, and
Coccidioidomycosis.
4. The protozoal cause is Leishmaniasis.
5. Chemical causes are hair dyes, nickel salt, chromium, potassium
dichromate, silicosis, and berylliosis.
6. Drugs causes are penicillin and neomycin.
7. Crohn’s disease.
8. Schistosomiasis.
9. Sarcoidosis |
| Why does DTH evolve? | ➢ DTH evolved as a protective host mechanism to combat
various intracellular pathogens, including mycobacteria,
virus, fungi, and certain parasites; however, excessive
DTH responses can lead to immunopathology, exhibited
by granuloma formation, fibrosis or even tissue necrosis.
➢ DTH reactions are prominent in autoimmune diseases,
tumor immunity and transplant rejection |
| What is tuberculin test? | ➢ A classic example of delayed type IV HS is the Mantoux
tuberculin test.
➢ Small amounts of tuberculin—a complex mixture of
peptides and carbohydrates derived from M.
tuberculosis—are injected intradermally
➢ The tuberculin test is used to determine whether an
individual has previously been infected
with Mycobacterium tuberculosis (A previously infected
individual would harbour reactive T cells in the blood).
➢ In individuals who have previously been exposed to the
bacterium, either by infection with the pathogen or by
immunization with BCG, an attenuated form of M.
tuberculosis, a local T cell-mediated inflammatory
reaction evolves over 24–72 hours |
| How is presentation of positive TB test? | ➢ If a tissue sample from the site of the positive reaction is
examined, it will show infiltration by lymphocytes and
monocytes, increased fluid between the fibrous
structures of the skin, and some cell death.
➢ If the reaction is more severe and prolonged, some of the activated macrophages will have fused together to form large cells containing several nuclei. An accumulation of activated macrophages of this sort is termed a granuloma
➢ The DTH response in the skin is determined by the extent of induration.
➢ Erythema indicates an immediate HS reaction and begins earlier than induration but often persists even after
induration has developed
➢ DTH skin test to most antigens is read as positive when
induration is 5mm or more at 48 hours and 72 hours
following inoculation.For tuberculin, 10 mm is considered a positive |
| How is reading of tb test? | ➢ The reaction is read by measuring the diameter of
induration (palpable raised, hardened area) across the
forearm (perpendicular to the long axis) in millimeters.
➢ If there is no induration, the result should be recorded as
"0 mm".
➢ Positive responses require the subject's exposure to the
Ag at least 4-6 weeks prior to skin testing.
➢ The lack of a DTH response to a recall Ag is often
regarded as an evidence of anergy.
➢ In the absence of underlying diseases, anergy may
indicate primary or secondary T-cell immunodeficiency
➢ The same cell-mediated mechanisms are elicited by
an actual infection with the living microbes, in
which case the inflammatory response continues,
and the ensuing tissue damage and granuloma
formation can cause serious damage |
| How is TB test different from actual microbe? | Moreover, in an actual infection, the microbes are often
present inside the macrophages and are not necessarily
localized in the skin. Large granulomas develop when the
stimulus persists, especially if undegradable particulate
materials are present and several macrophages, all attempting to ingest the same material, have fused their cell membranes to one another
Although granuloma formation may be an effective method
the immune system employs to sequester indigestible
materials (whether of microbial origin or not ) from the rest of the body, the harm inflicted by this immune mechanism may be much more serious than the damage caused by the infectious organisms diseases as pulmonary tuberculosis and schistosomiasis and in certain fungal
infections that become established within the body
tissues rather than at their surface |
| What are two phases of Th1 HS? | Sensitisation (TH1 cells that are activated by intracellular pathogens, including bacteria, fungi and protozoa, as well certain chemicals ( hair dyes, nickel salts) leading to clonal expansion and differentiation of antigen-specific cells into TH1 clone, CD4+ TH1 cells secrete IL2 and interferon gamma, further inducing the release of other TH1 cytokines, thus mediating the immune response)
Effector phase ( Antigen-specific TH1 cells that were primed by a previous exposure to the antigen, enter the site
of antigen injection, recognize complexes of peptide:
MHC class II molecules on APCs, undergo further clonal
expansion and release inflammatory cytokines, such
as IFN-γ, TNF-β) |
| How is delayed type HS? | Activation of macrophages increases their
production of toxic oxygen radicals, nitric oxide, and
hydrolytic lysosomal enzymes enabling the killing of
microbes within their phagolysosomes/ tissue
damage.
transform into multinucleated giant cells, whereas activated CD8+T cells destroy target cells on contact causing tissue injury, typically called delayed-type HS
Activated macrophages secrete proinflammatory cytokines
such as TNF-α, IL-1, and IL-6 ===> Leaky endothelial barriers => more immune cells => edema, redness and fever
These cells release mediators (chemokines and
cytokines) that activate local endothelial cells, recruiting
an inflammatory cell infiltrate
Each of these phases takes several hours and so the fully
developed response appears only 24–48 hours after
challenge |
| What is characterstic of TIVHS Tuberculous granuloma? | The characteristic histologic appearance of the macrophage–T-cell infiltrate is a granuloma.
➢ This type of infiltrate in the tissue is called granulomatous inflammation
➢ One of the main features of the immune response to M.
Tuberculosis is the formation of an organized structure
called granuloma.
➢ Following inhalation of contaminated aerosols,
M. Tuberculosis moves to the lower respiratory tract
where it is recognized by alveolar macrophages
➢ M. tuberculosis are engulfed by macrophages after being identified as foreign, but due to an immuno-escape
mechanism peculiar to mycobacteria no degradation
➢ Thereby TB can continue to replicate within
macrophages.
➢ Granulomas form when an intracellular pathogen or its
constituents cannot be totally eliminated. |
| How does tuberculous granuloma develop? | ➢ When mycobacteria (red) resist the effects of
macrophage activation, a characteristic localized
inflammatory response called a granuloma develops.
➢ This consists of a central core of infected macrophages.
➢ The core may include multinucleated giant cells, which
are fused macrophages, surrounded by large
macrophages often called epithelioid cells.
➢ Although in the first instance the granuloma acts to
constrain the infection, some bacilli can actually survive
for decades inside these structures in a dormant state
➢ Mycobacteria can persist in the cells of the granuloma.
➢ The central core is surrounded by T cells, many of which
are CD4-positive.
➢ The exact mechanisms by which this balance is achieved,
and how it breaks down, are unknown. |
| How is TB reactivation? | ➢ Due to some environmental (e.g., HIV infection,
malnutrition etc.) or genetic factors, the bacteria will
reactivate in 10% of the latently infected individuals and
provoke the death of the infected macrophages
➢ A necrotic zone (called caseum due to its milky
appearance) will develop in the centre of the granuloma
➢ Ultimately the structure will disintegrate allowing exit of
the bacteria, which will spread in other parts of the lungs
and more lesions will be formed.
➢ Infection will also be transmitted to other individuals due
to release of the infected droplets by coughing |
| How is sarcoidosis? | ➢ Granulomas also form in the lungs and elsewhere in a
disease known as sarcoidosis, which may be caused by
occult mycobacterial infection
➢ Sarcoidosis is a multisystem disorder characterized
by non-caseating granulomatous inflammation.
➢ It is classified as either acute or chronic – the former
does not necessarily precede the latter form
➢ Acute sarcoidosis (approx. ⅓ of the cases) has an
abrupt onset, with constitutional symptoms but is selflimiting after a few years.
Other manifestations include cough, dyspnea, anterior
uveitis, erythema nodosum, and arthralgia |
| How is onset of chronic sarcoidosis? | ➢ Chronic sarcoidosis has a gradual onset and is often
asymptomatic in the early stages although it primarily
affects the lungs.
The first symptoms usually include
exertional dyspnea and a dry cough, with
mild rales on pulmonary examination.
Other characteristic systemic manifestations are also
possible.
➢ Common symptoms, which tend to be vague, include fatigue (unrelieved by sleep), lack of energy, weight loss, joint aches and pains, arthritis, dry eyes, swelling of the knees, blurry vision, shortness of breath, a dry, hacking cough, or skin lesions |
| How is pathophysiology of sarcoidosis? | Granulomatous inflammation is characterized primarily by
accumulation of monocytes, macrophages, and activated Tlymphocytes, with increased production of key inflammatory
mediators, TNF, IFN-γ, IL-2, IL-8, IL-10, IL-12, IL-18, IL23 and TGF-β, indicative of a Th1-mediated immune response. |
| How is testing for sarcoidosis? | A chest x-ray is the most appropriate initial test in a
patient with suspected sarcoidosis.
➢ Although chest x-ray may show classic parenchymal
disease with bilateral hilar lymphadenopathy, it is
important to note these features are not always evident.
➢ High-resolution CT may be particularly helpful for
distinguishing active inflammation from irreversible
fibrosis in selected patients with stage 2 or 3 sarcoidosis
➢ A biopsy is the gold standard to confirm the diagnosis.
➢ Typical histopathological findings include the presence
of non-caseating granulomas with giant cells.
Feature: GRUELING |
| How is tx of sarcoidosis? | ➢ Glucocorticoid therapy is indicated with disease
progression, or if certain organs, such as the eyes or
heart, are affected.
➢ While spontaneous remission is frequent during the early
stages of sarcoidosis, irreversible lung fibrosis may
develop as the disease recurs or progresses |
| What is atopic dermatitis? | Atopic dermatitis (AD) is the most common chronic
inflammatory skin disease, with a prevalence of up to 7%
in adults and up to 25% among children.
➢ Characteristically, symptoms start within the first 5 years
of life, and in adults the disease has generally been
present for decades
➢ AD is a chronic relapsing genetically predisposed
inflammatory skin disease characterized by intense
pruritus and by scaly, dry eczematous lesions; it is often
associated with other atopic disorders, such as allergic
rhinitis and asthma
➢ Although IgE has a role on the formation of allergic
rhinitis and some forms of allergic asthma, there are few
publications in the literature that IgE has a major role on
the pathogenesis of AD |
| How is presentation of atopic dermatitis? | ➢ A prolonged IgE-induced reaction
causes atopic dermatitis, a skin condition characterized
by persistent itching and scaly red patches.
➢ These often develop at sites where the skin is bent, such
as the elbows and knees
➢ The persistence is due to the influx of mast cells and
mainly eosinophiles stimulated by the continued
presence of the allergen, which is often a harmless
substance such as animal hair or dander.
➢ AD is now understood to be a much more heterogeneous
disease, with additional activation of TH22, TH17/IL-23,
and TH1 cytokine pathways depending on the subtype of
the disease |
| How is allergic contact dermatitis? | ➢ DTH responses in the skin can also occur as contact
hypersensitivity (CH)
➢ Allergic contact dermatitis (ACD) is a common
inflammatory skin disease presenting with pruritic,
eczematous lesions.
➢ ACD is common in the general population and is the
most frequent occupational skin disease
➢ Its etiology may be suggested by the body sites of
involvement, history of exposure, and morphology and
distribution of the skin lesions.
➢ ACD results from a T cell-mediated, DTH reaction elicited
by the contact of the skin with the offending chemical in
individuals who have been previously sensitized to the
same chemical |
| What are clinical manifestations of ACD? | ➢ The clinical manifestations of ACD are the result of a T
cell-mediated inflammatory reaction occurring in the skin
upon re-exposure to the offending hapten (elicitation
phase) and mediated by the activation of hapten-specific
T cells in the skin.
➢ The primary effector cells of ACD appear to be CD8+ cells.
➢ The inflammatory reaction occurs 48 to 72 hours after
exposure.
➢ REGULATORY MECHANISMS OF ACD — Regulatory T
cells (Treg) may have a role in the sensitization and
elicitation phase of ACD and in the down regulation of
the inflammatory response
➢ Contact dermatitis is a common inflammatory skin
condition characterized by erythematous and pruritic
skin lesions after contact with a foreign substance |
| How is contact HS? | The most common substances that cause contact
dermatitis include:
– Poison ivy, Poison oak
– Nickel, and
– Fragrances
What is urushiol?
➢ Urushiol is an irritating, oily sap found in all parts of
poison ivy, poison oak, and poison sumac plants,
including the leaves, stems, and roots.
➢ It's even there after the plant has died.
➢ Urushiol is absorbed quickly into the skin.
Poison Ivy: ➢ The rash produced by contact with poison ivy is caused by a T-cell response to a chemical in the poison ivy leaf called pentadecacatechol.
➢ This compound is lipid-soluble and can therefore cross
the cell membrane and modify intracellular proteins |
| What is presentation of contact HS? How is nickes CD | ➢ The hallmark of the diagnosis of poison ivy is linear
dermatitic lesions.
➢ The possibility of an external cause of dermatitis
always must be considered if the dermatitis is linear
or sharply defined
Nickel
➢ Important DTH responses to divalent cations such as
nickel have also been observed.
➢ Nickel is a component of many different types of metals,
including white gold, German silver, nickel and gold
plating, solder, and stainless steel.
➢ Unilateral nickel-induced facial dermatitis elicited by cell
phone use has been reported.
➢ Hairdressers have been diagnosed with allergy-related
hand eczema from prolonged skin contact with nickelcontaining scissors |
| How do fragrances cause contact HS? | ➢ Of the approximately 2,500 fragrance ingredients
currently used in perfumes, at least 100 are known
contact allergens.
➢ In addition to perfumes, these fragrances are used in
cosmetics, shampoos and other hair products, soaps,
moisturizers, and deodorants.
➢ ACD caused by fragrance occurs predominantly in
women with facial or hand eczema
Eyelid dermatitis
➢ Individuals may develop dermatitis on eyelids and other
exposed skin following exposure to airborne allergens or
allergens transferred to that site by the fingers.
➢ Contact dermatitis may also result from allergy to eyelid
makeup |
| How is allergic contact dermatitis to rubber? | ➢ ACD to rubber is caused by a type IV reaction and is the result of exposure to the accelerators present in rubber products in sensitive individuals.
➢ ACD due to synthetic rubber gloves occurs even with the use of latex-safe products. (Individuals may have ACD to chemicals added to rubber gloves).
➢ An allergic reaction to vinyl gloves is not likely and is considerably rare
➢ Individuals experiencing this type of reaction typically
develop localized erythema, pruritus, and urticarial lesions 48 hours after exposure.
➢ Incorrectly labelling this problem as latex allergy and
recommending nonlatex rubber substitutes (eg,
hypoallergenic gloves) likely will not be effective, as these
nonlatex replacement products contain the same accelerators as do latex gloves. |
| What is true latex allergy? | ➢ The most severe form of latex allergy, often referred to as true latex allergy, is caused by a type I (immediate) hypersensitivity reaction mediated by immunoglobulin E (IgE) antibodies.
➢ Individuals experiencing this type of reaction have a systemic response to latex proteins that may result in fulminant anaphylaxis.
➢ Individuals with true latex allergy must absolutely avoid latex products, and substituting nonlatex products is the most
effective approach |
| What are occupational dermatitis? | ACD in response to workplace materials may improve
initially on weekends and during holidays, but individuals
with chronic dermatitis may not demonstrate the classic
history of weekend and holiday improvement.
Most allergens rarely sensitize a high percentage of the
population
Irritant contact dermatitis is more likely if multiple
workers are affected in the workplace |
| How do medications cause contact HS? | ➢ Medications are important causes of allergic contact
dermatitis (Antibiotics, such as neomycin rubbed on the
surface of the skin).
➢ Some insect proteins also elicit DTH response. However,
the early phases of the host reaction to an insect bite are
often IgE-mediated or the result of the direct effects of
insect venoms. |
| How is ACD hx and presentation? | ACD usually leads to erythema and scaling with visible
borders.
➢ Itching and discomfort may also occur.
➢ Acute cases may involve a dramatic flare with erythema,
vesicles, and bullae; chronic cases may involve lichen
with cracks and fissures.
➢ Only history and questioning can determine whether the
materials to which a patient is allergic are partly or wholly
responsible for the current dermatitis.
➢ When a possible causative substance is known, the first step in confirming the diagnosis is determining whether the
problem resolves with avoidance of the substance |
| What test for ACD? | Patch test |
| What is celiac disease? | ➢ Gluten is a protein commonly found in wheat, rye, barley
and other grains
➢ Both celiac disease and allergy (type I HS) can be
triggered by gluten proteins although these responses
involve different immunological mechanisms
➢ Celiac disease is classified as a Type IV HS mediated by Tcell responses whereas allergy is usually classed as a
Type I HS mediated by E-type Igs (IgE antibodies).
➢ Celiac disease serves as the best example of delayed HS
reactions associated with foods. Celiac disease results from
activation of both a cell-mediated (T-cell) and humoral (B-cell) immune response. This activation results from exposure to the glutens |
| How is pathophysio of celiac disease? | ➢ While the etiology and pathophysiology of the disease
are not fully understood, the condition is considered to
be caused by a combination of genetic, environmental,
and immunological factors.
➢ This enteropathy is a cell-mediated, localized
inflammatory reaction occurring in the intestinal tract
upon provocation with ingested gluten. The inflammatory
reaction results in a so-called 'flat lesion' in the gut.
➢ Celiac disease is an intestinal immune-mediated
enteropathy precipitated by exposure to dietary gluten in
genetically predisposed individuals.
➢ Celiac disease tends to cluster in families. However, the
inheritance pattern is unknown
➢ When people who have celiac disease consume gluten,
their immune system responds by damaging the
fingerlike villi in the small intestine prevent absorption |
| What are S&S of celiac disease? | Gastrointestinal symptoms
Gastrointestinal symptoms may include the following:
Diarrhea Bloating, Constipation, Weight loss; in infants and young children with untreated celiac disease, failure to thrive and growth retardation are common. Weakness and fatigue; usually related to general poor nutrition, Severe abdominal pain
Extraintestinal symptoms may include the following:
Anemia Osteopenia and osteoporosis Joint pain Headache Neurologic symptoms
Skin disorders; including dermatitis herpetiformis, a
condition with pruritic, papulovesicular skin lesions
involving the extensor surfaces of the extremities, trunk,
buttocks, scalp, and neck
Hormonal disorders - Including amenorrhea, delayed
menarche, and infertility in women and impotence and
infertility in men |
| What are tests for celiac disease? | Before a physician performs an intestinal biopsy, blood
work are ordered as part of the screening process.
Before the blood work, the patient must eat glutencontaining foods for a certain period of time to achieve more accurate results.
➢ These patients have antibodies to gliadin, as well
as autoantibodies to endomysium, reticulin, and
tissue transglutaminase (the antibody trinity of coeliac
disease).
➢ The blood tests considered most effective to indicate
possible celiac disease include tissue transglutaminase
antibody (tTG) immunoglobulin A (IgA) and total IgA.
➢ The IgA test is performed because an IgA deficiency is
common in celiac patients. |
| What is gold STD for celiac disease dx? | ➢ Gold Standard for Diagnosing Celiac The gold standard for diagnosing celiac disease should be an endoscopy with a duodenal biopsy.
The biopsy should involve taking samples of the duodenum (measure the degree of villous atrophy
➢ Biopsy of small bowel showing celiac disease manifested
by blunting of villi and lymphocyte infiltration of crypts |
| How is tx of celiac disease? | ➢ The only known treatment for celiac disease is to follow a
gluten-free diet for life. Even the smallest amount of
gluten can trigger an immune response
Among autoimmune disorders, increased prevalence of
CD has been found in patients with autoimmune thyroid
disease, type 1 diabetes mellitus, autoimmune liver
diseases and inflammatory bowel disease.
Patients with CD have modest increases in risks of
malignancy (intestinal cancer) and mortality compared to
controls |
| What are some other examples of DTH? | ➢ Temporal arteritis
➢ Hashimoto's thyroiditis
➢ Symptoms of leprosy
➢ Graft-versus-host disease
➢ Chronic transplant rejection |
| How is hashimotos? | ➢ A blood test may confirm the presence of antibodies
against thyroid peroxidase (TPO antibodies), an enzyme
normally found in the thyroid gland that plays an important role in the production of thyroid hormones |
| How is clinical features of DTH? | ➢ The clinical history of DTH reactions differs depending on
the etiology.
➢ The physical examination findings can be normal, or they
can reveal the signs and symptoms of the specific
disease.
➢ Laboratory Studies, Imaging Studies, Skin biopsy may be
indicated
Medical Care
➢ Medical treatment is specific for the disease entity.
Complications
➢ Secondary infections such as cellulitis can occur.
Prognosis
➢ The prognosis for delayed-type hypersensitivity reactions
is related to the disease entit |
