Final Patho Integumentury/Immunodeficicney/Inflammation

epidermis

Although there is an increased variation in epidermal thickness, the average number of cell layers remains unchanged.

The prickle cells of the inner layer of the epidermis show greater variation in nuclear and cytoplasmic size with a less orderly arrangement of cells

thickening in sun-exposed areas.

epidermis

contains blood vessels, nerves, hair follicles, and sebaceous glands,

but the major portion is composed of collagen and elastin.

elasticity of the skin largely results from dermal elastin.

Decreased skin strength and elasticity with aging are attributed to a decreased amount of elastin and a proportionate increase

in the collagen-to-elastin ratio.

Dermis

Collagen fibers change with age, becoming cross-linked and rearranged into thicker bundles.

This condition is called elastosis and is closely associated with exposure to sunlight (solar elastosis).

It produces a weather-beaten or tanned appearance.

There is greater vascular fragility,

leading to the frequent appearance of hemorrhages (senile purpura); cherry angiomas; venous stasis; and venous lakes on the ears, face, lips, and neck.

(senile purpura); cherry angiomas; venous stasis; and venous lakes on the ears, face, lips, and neck.

(ecchymoses) on the skin of older individuals, typically on the forearms and backs of the hand

The decreased vascularity and circulation in the dermis and the underlying subcutaneous tissue also have an effect on drug absorption.

Drugs administered subcutaneously are absorbed more slowly, thus prolonging their half-life. The amount of subcutaneous fat tissue also decreases, especially in the extremities, so that arms and legs appear to be thinner.

Unopposed adrenal androgens

produce coarse facial hair in 50% of White women older than 60 years, especially on the chin and around the lips.

The decrease in sebum secretion and in the number of sebaceous glands

results in the drier, coarser skin associated with aging.

Sweat glands generally decrease in size, number, and function with age.

In the eccrine glands, the secretory epithelial cells become uneven in size, ranging from normal to small,

and there is a progressive accumulation of lipofuscin in the cytoplasm (yellowish-brown, age-related pigment that accumulates in cells)

In the very old, the secretory coils of many eccrine glands are replaced by fibrous tissue, which drastically diminishes their capacity to produce sweat.

The thermal threshold for sweating is raised so that the amount of sweat output at a body temperature of 38°C (100.4°F) decreases

This may be because there are fewer blood vessels and nerve cells around the glands that enable the body to respond to temperature changes.

Apocrine glands do not decrease in number or size, but they do decrease in function.

An accumulation of lipofuscin has also been noted in apocrine glands.

The diminished functioning of sweat glands in the elderly greatly impairs the ability to maintain body temperature homeostasis.

The glandular function of skin varies considerably with age.

Young children and elderly adults have fewer functional sweat glands and therefore less efficient evaporative heat loss capabilities.

Sebaceous glands are particularly active during puberty, causing a predisposition to acne;

they become less active with age, causing a predisposition to dry skin.

Inflammatory disorders of the skin

individuals who have hypersensitivity reactions to substances in the environment.

Infectious agents

ranging from viruses to insects may infect the skin.

Proliferative conditions include

psoriasis, seborrheic keratosis, cysts, warts, and papillomas.

Most HSV-1 infections occur above the waist.

result when external infection is spread to other parts of the body through the occupational hazards that exist in professions such as dentistry and medicine and some athletics

Herpesvirus lesions usually begin with a burning or tingling sensation.

Vesicles and erythema follow and progress to pustules, ulcers, and crusts before healing.

The lesion is most common on the lips, face, and mouth. Pain is common, and healing takes place in 10 to 14 days

After the initial infection, the herpesvirus persists in latent form in the trigeminal nerve and other ganglia.

Recurrent lesions are common

May be precipitated by stress, sunlight exposure, menses, or injury.

vast majority of patients have at least one episode of herpesvirus reactivation, and some individuals may have 10 or more outbreaks per year.

Recently concern has arisen over the identification of infectious viral shedding in the absence of symptomatic lesions.

Herpes zoster (shingles) is an acute localized inflammatory disease of a dermatomal segment of the skin (Fig. 53.6).

It is caused by the same herpesvirus that causes chickenpox (varicella zoster virus).

It is believed to be the result of reactivation of a latent varicella zoster virus that has been present in the sensory dorsal ganglia since childhood infection.

During an attack of shingles, the reactivated virus travels from the ganglia to the skin of the corresponding dermatome.

HSV migrates

along trigeminal nerve to sensory ganglion and remains in latent state

then the lesion where the virus was is healed

HSV recurrence

HSV is activated

migrates from sensory ganglion back along trigeminal nerve to mucocutaneous site, replicates, and new lesion develops

Skin cancer most common malignancy in the United States; however, with the

EXCEPT of malignant melanoma and a few squamous carcinomas, skin cancers are not life threatening.

Ultraviolet light damages sun-exposed skin and

is a major factor in the development of skin cancer.

Although many of the disorders described in the following section are not life threatening, they can affect the quality of life.

Atopic dermatitis is a complex genetic disease that results from gene–gene and gene–environment interactions.

Genetic defects in the epidermal barrier protein filaggrin have been cited as a major cause of atopic dermatitis.

excema

type 1 hypersensivitity

The stratum corneum layers of those individuals with loss-of-function mutations in the filaggrin gene have lower levels of natural moisturizing factor and also are deficient in extracellular lipids including ceramides.

It is suggested that the trait is inherited via a maternal gene located on chromosome 11.

Atopic dermatitis

treatment of atopic dermatitis

repair of barrier function

Atopy, or allergy, is indicated by a personal and sometimes family history of

asthma, allergic rhinitis, or the most commonly seen manifestation, eczematous dermatitis

children- erythema, papules, and lichenification of the flexor surfaces of the extremities, antecubital,popliteal areas, the wrists, and the nape of the neck.

Older children and young adults have thickening of the skin, or lichenification, along with fine, dry scaling and some papules seen on the flexor surfaces of the extremities and the scalp, face, and upper chest.

Retrospective studies show that in nearly half of all patients with childhood atopic dermatitis, the disease improves or clears with age.

active irritants: acids, alkalis, and hydrocarbons.

Contact dermatitis is a cutaneous reaction to topical irritation or allergy.

Irritant contact dermatitis develops in any person exposed to a sufficiently high concentration of the irritating agent.

Allergic contact dermatitis

indicates delayed acquired hypersensitivity to a specific allergen.

Allergic contact dermatitis indicates delayed acquired hypersensitivity to a specific allergen.

Dermatologic problems may appear after years of asymptomatic exposure to the precipitating agent.

Chromates, nickel, ethylenediamine, paraphenylenediamine, neomycin, formaldehyde, and lanolin components

may cause allergic contact dermatitis.

Aside from reactions to various industrial chemicals,

the most common type of allergic contact dermatitis reaction is to plants

allergy to poison ivy, poison oak, and poison sumac

Rhus dermatitis

Clinically, rhus dermatitis begins within 48 hours of contact.

The first symptom is pruritus, followed by erythema and vesicle formation, sometimes in linear fashion (Fig. 53.19).

rhus dermatitis

As long as the allergen remains on the surface of the skin, it can be spread to nonexposed areas.

Washing can help to prevent spread by hand contact. Exposure to blister fluid does not spread poison ivy lesions.

massive collagen deposition with fibrosis accompanied by inflammatory reactions and vascular changes in the capillary network.

may represent an autoimmune mechanism or primary vasculopathy.

Scleroderma

Localized scleroderma

(morphea) is a benign disease

diffuse scleroderma

(progressive systemic sclerosis) is serious, progressive, and fatal.

Localized scleroderma

Disability is confined to the area involved.

Lesions tend to involute (shrivel) slowly and spontaneously. Relapses are rare.

Localized scleroderma

Primary skin lesions are single or multiple, violet-colored, firm, inelastic macules and plaques that enlarge slowly.

The progressing border retains a violet hue, and the center becomes whitish and slightly depressed beneath the skin surface.

Bizarre lesions occur, such as long linear bands on extremities, “saber cut” lesions in the scalp, or lesions involving one side of the face or the body.

Localized scleroderma

Secondary lesions include mild or severe scarring after healing, permanent hair loss from the scalp lesions, and, rarely, ulceration.

The trunk, extremities, and head are most frequently involved

Diffuse scleroderma is a rare systemic collagen disease of unknown cause

characterized by a long course of progressive disability resulting from lack of mobility of the areas and the organs affected.

Diffuse scleroderma

The skin becomes hardened like hide

the esophagus and the gastrointestinal tract semirigid, the lungs and heart fibrosed, the bones resorbed, and the overlying tissue calcified

Diffuse scleroderma

Another rare collagen disorder, dermatomyositis

characterized by the acute or insidious onset of muscle pain, weakness, fever, arthralgia, and, in some cases, a puffy erythematous eruption that is usually confined to the face and the eyelids.

Diffuse scleroderma

Progression of the disease

results in muscle atrophy and contractures, skin telangiectasias (vascular lesions formed by blood vessel dilation) and atrophy, and generalized organ involvement. Death occurs in 50% of cases.

basal cell carcinomas

most common skin tumors and the most benign (Fig. 53.29).

Squamous cell carcinomas are the second most common skin malignancy (Fig. 53.30). They can occasionally metastasize.

By contrast, melanoma is rare but can be highly malignant (Fig. 53.31). Melanoma is notoriously unpredictable;

however, the prognosis is based on the size, the depth of invasion of the tumor, and the presence of metastasis.

Lumps that increase rapidly in size, change color, ulcerate, or bleed should undergo biopsy and be examined microscopically to rule out malignancy.

Complete surgical excision is the treatment of choice for skin cancers.

Kaposi sarcoma

arises from reticulocytes and is multifocal, metastasizing, and malignant.

opportunistic neoplasm that commonly occurs in individuals with immunosuppression, particularly those with HIV/AIDS. It presents as purple or brown lesions on the skin and can affect internal organs.

opportunistic neoplasm

it occurs in persons with preexisting immunodeficiency,

for example, individuals with primary immunodeficiency, persons who undergo therapeutic immunosuppression, and persons with human immunodeficiency virus (HIV) infection.

KAPOSI Sarcoma

Causes outbreaks in the eye even if there's no cold sore present (also can relate to conjuctivitis)

HSV can lie dormant in nerves and reactivate

to cause Herpes Simplex Keratitis.

Events in the inflammatory response to bacterial antigens and tissue injury include

(1) vasodilation and increased vascular permeability, (2) recruitment and emigration of leukocytes, and (3) phagocytosis of antigens and debris.

Innate immune cells, including neutrophils, macrophages, and some tissue cells, are equipped with pattern recognition receptors that allow them to bind to foreign particles

and produce inflammatory cytokines that are released to initiate inflammatory cascades

Pattern recognition receptors, such as mannose receptors and Toll-like receptors, have been known to be present on the cell membrane for some time, but now their presence inside of cells has been described (see Table 9.2 and Fig. 9.10).

Pattern recognition receptors are able to recognize approximately 1000 different pathogen-associated molecular patterns (PAMPs) and damage-associated molecular patterns (DAMPs) (Table 9.4).

When the internal receptors detect foreign matter, such as viral RNA or DNA, an internal cascade of events can assemble a group of proteins into a functional unit called an inflammasome.

Caspase-1 is an important component of the inflammasome that increases the production and release of IL-1, an important proinflammatory cytokine that causes fever and contributes to recruitment and activation of immune cells.

Prostaglandins and leukotrienes are important mediators of inflammation (Table 9.5).

Mast cells are an important source of these inflammatory chemicals.

Mast cells in the area of injury degranulate and release packets of histamine and other inflammatory chemicals

. One of the early actions of these mediators is to vasodilate and cause endothelial cells to begin retraction and rounding up, thus increasing capillary permeability.

The greater volume of blood increases the amount of pressure within the blood vessels

(hydrostatic pressure).

The increased pressure along with increased permeability pushes fluid out of the blood vessels and into the surrounding tissue, contributing to local swelling.

Because of the dilated blood vessels and open capillaries, more blood is carried to the injured area and contributes to the redness, pain, heat, and swelling of inflammation

Histamine is an early mediator of this inflammatory response.

It is such a potent vasodilator that it can cause significant reductions in blood pressure when released in excessive amounts.

also causes bronchial constriction and mucus production

Histamine (neurotransmitter)

Histamine receptor–blocking agents are widely used in allergic reactions, such as skin reactions and hay fever,

to suppress these inflammatory actions of histamine.

Chemotactic factors are substances that stimulate directional movement, or migration, of cells along a concentration gradient.

In inflammatio they cause pain and the release of

vasodilaiton, increased permiability, and swelling

Because of the dilated blood vessels and open capillaries, more blood is carried to the injured area

and contributes to the redness, pain, heat, and swelling of inflammation (Fig. 9.20).

tissue damage then

release of vasoactive and chemotactic factors causes

vasodilation, increased permeability, and neutrophil mitigation

cardinal signs of inflammation have been described

1) redness (rubor), (2) swelling (tumor), (3) heat (calor), (4) pain (dolor), and (5) loss of function (functio laesa).

the “first line of defense” because they are frequently the initial sites of microbial invasion.

Intact epithelia in skin and mucous membranes provide mechanical and chemical barriers that prevent microorganisms from gaining access to the body’s tissues.

The skin epithelium produces antimicrobial peptides called defensins that can kill a wide variety of bacteria and fungi

The intestinal epithelium produces another form of bactericidal peptide called

cryptocidins that prevent bacteria from colonizing the intestinal wall.

mature in the thymus, have two major subgroups:

T cells

T helper cells and cytotoxic T cells.

Two major subgroups of T cells that play crucial roles in the immune response, with T helper cells assisting other immune cells and cytotoxic T cells directly killing infected or cancerous cells.

Activation of T helper cells results in secretion of the cytokines necessary for clonal expansion of T and B lymphocytes.

T helper cells perform a central role in specific immunity

Cytotoxic T cells

locate and lyse abnormal cells through the actions of perforins.

T cells DEVELOP/mature

thymus

The thymus is relatively large at birth

and steadily atrophies after puberty

Cells displaying foreign antigens stimulate an immune response,

whereas those displaying self antigens do not because self-reacting T cells are not allowed to survive in the thymus

cells are screened during development in the thymus so that they recognize self MHC proteins

and do not react to self peptides displayed by self MHC proteins.

A rigorous selection process occurs in the thymus such that self-reactive T cells are eliminated.

In the first, T cells must demonstrate an ability to recognize self MHC proteins displayed on the surface of specialized thymic cells.

Portions of the TCR must make appropriate contact with the MHC protein, or the T cell will not be able to respond to antigens presented on the cell surface.

Expression of either CD4 or CD8 on the T cell helps to determine which class of MHC the T cell must fit. T cells that do not have functional TCRs undergo apoptosis in the thymus.

The “epitope spread” theory states that

recurrent infection or damage to a particular organ causes the immune system to develop multiple autoantibodies.

Leads to autoimmune reactions against various self-antigens.

Theories attributing autoimmunity to thymus gland defects state that maturation and differentiation of T cells

are affected either by decreased hormone secretion or by failure of the thymus to expose T cells to all self products.

The thymus gland is responsible for exposing developing T cells to self products produced in the thymus or carried to the thymus gland

If some self products are not exposed to the developing T cells, the product will not be recognized as self and will subsequently be attacked.

Primary disorders are immune deficiencies

not attributable to other causes; these may be congenital or acquired.

Persons with a primary immunodeficiency can be predisposed to multiple deficiencies, as in agammaglobulinemia or SCID,

or can have a single phenotype deficiency predisposing to a specific problem, as in patients with STAT-1–dependent chronic mucocutaneous candidiasis

Secondary immunodeficiency disorders

are a consequence of non–immune system disorders or treatments that secondarily affect immune function.

Examples of secondary disorders

associated with hyperlipidemia or malnutrition, medical treatments such as cancer chemotherapy, or biopsychosocial stress such as postsurgical immune suppression or psychological stress.

primary congenital immunodeficiency disorders

genetic disorders that are often sex linked and occur in 1 in 58,000 infants.

PIDs include congenital phenotypes that result from abnormal development or maturation of immune cells

as well as acquired primary disorders of immune cells such as HIV/AIDS.

A number of physical, psychosocial, nutritional, environmental, and pharmacologic factors can singly or in combination

lead to the development of secondary immunodeficiency disorder

The direct and indirect linkages between the brain and the endocrine and immune systems are well known. As a result, excessive neuroendocrine responses

such as elevated cortisol levels, can lead to disease. CUSHINGS

(secondary immunodeficincy)

For example, an excessive neuroendocrine response to stress with increased secretion of corticosteroids boosts a person’s susceptibility to infectious agents and tumors.

Individuals experiencing physical and psychosocial stress, decreased social support, depression, and bereavement show decreased immune system functioning.

morbidity and surgery also affect the function of the immune system. After surgery, T- and B-cell numbers decrease.

this temporary deficiency can last up to 1 month and is most likely a result of the stress of surgery

secondary immune defiiciency

Cytotoxins and other cancer pharmacotherapeutic drugs cause a state of generalized immunosuppression, including growth retardation, susceptibility to infection, impaired wound healing, and hypertension.

A number of pharmaceuticals affect the functioning of the immune system.

secondary immune defiiciency

Malnutritional states can lead to protein depletion as well as carbohydrate, lipid, vitamin, and mineral deficiencies.

Protein/calorie malnutrition causes T-cell reductions and dysfunction. Antibodies are composed of proteins, levels of which are also low in a state of depletion

Malnutrition, a major cause of immune system dysfunction,

leads to lymphocyte dysfunction and altered stem cell development.

Medications such as cytotoxins and other cancer pharmacotherapeutic drugs cause generalized secondary immunosuppression.

However, other medications, such as anesthetics, alcohol, antibiotics, and steroids, also affect the immune response and can lead to secondary immunosuppression.

A secondary infection is a bacterial or viral illness that develops following a first illness.

The second infection may develop because a person's immune system is stressed or weakened. The secondary infection may prolong the first infection or make it more severe

prolonged inflammation may impair healing

and result in an accumulation of macrophages, fibroblasts, and collagen, called a granuloma.

chronic inflammation

Granulomas are usually evident on examination of tissue biopsy as clusters of macrophages surrounding particulate matter or resistant microbes such as Mycobacterium tuberculosis.

Fibrosis and scarring are evident because normal parenchyma is replaced with fibrous tissue.

Inflammation is an important aspect of innate immunity that involves localization of harmful agents and the movement of phagocytic cells to the area. Classic manifestations of inflammation are redness, swelling, heat, pain, and loss of function.

Inflammatory chemicals such as histamine, prostaglandins, and leukotrienes are released from injured tissues, mast cells, macrophages, and neutrophils. These chemicals increase vascular permeability, vasodilate, and attract immune cells to the area (chemotaxis).