CASE 8

CARBUNCLE
General Pathology: Cell Adaptation Cell Injury and Death Inflammation Tissue Healing and Repair Haemodynamic Disorder Microscopic Features Immunity Process Infectious Disease

TIM AKADEMIK DIVISI SOOCA SPEKATRIA

CASE REVIEW

Mr. Carbun, 20 years old

CC : Fever Since 2 Days Ago

History Taking :
Pain, swelling, and burning sensation in buttock since 3 days ago Lesion ruptured this morning Bloody pus come out

Physical Examination :
Body Temperature : 380C Head and Neck : Normal Gluteal Region : Red Solitary Nodule, 2 cm in diameter Ulcer (+), 0,5 cm in diameter Discharge (+) bloody pus

Lab Examination :
Leukositosis

Diagnosis : Carbuncle

Pharmacology Non Pharmacology

Treatment : : Antibiotic : Took blood for culture examination

Prognosis : After 1 week : Lesion healed After 4 weeks : Scar in buttock

Homeostasis

CONCEPT MAP

Infection by Staphylococcus aureous

Failed cell adaptation

Cell injury

Inflammation (Acute)

Artery Dilation

Increased Vascular Permeability

Staphylococcus excrete exotoxin Secrete Cytokine

Blood into injury tissue

Blood into Normal Tissue

Liquid to interstitial Edema

Neutrophil fight the pathogen Pus

Secretion of Prostaglandin Stimulate cyclic adonosine monophosphate

Hyperemia Dolor

Local Calor Burning Sensation

Tumor Carbuncle Compensanting Loss of Leukocyte Cells Ulcer Producing of Leukocyte by Bone Marrow Tissue Repair Collagen in Wound Area

Fever Acceleration Release of Leukocyte

Stimulate Neurotransmitter

Bloody Pus

Leukocyte

Pain (Dolor)

Leukocytosis Scar Formation

CELL ADAPTATION

Normal cell tends to maintain their steady state, called homeostasis. As cells encounter physiologic stresses or pathologic stimuli, they can undergo adaptation, achieving a new steady state and preserving viability and function. The principal adaptive responses are hypertrophy, hyperplasia, atrophy, and metaplasia.

A. HYPERTROPHY
Hypertrophy is an increase in the size of cells resulting in increase in the size of the organ. The hypertrophied organ has no new cells, just larger cells. Occurs in tissue whose cell are incapable to divide Hypertrophy can be physiologic or pathologic and is caused either by increased functional demand or by specific hormonal stimulation. Hypertrophy and hyperplasia can also occur together, and obviously both result in an enlarged (hypertrophic) organ. Mechanisms: Hypertrophy is the result of increased production of cellular proteins. Example:

o Physiologic hypertrophy of the uterus during pregnancy, occurs as a consequence of estrogen-stimulated smooth muscle hypertrophy and smooth muscle hyperplasia. o Pathologic cellular hypertrophy of skeletal muscle and the heart can undergo only hypertrophy in response to increased demand because in the adult they have limited capacity to divide.

B. ATROPHY
Atrophy is reduced size of an organ or tissue resulting from a decrease in cell size & number. It should be emphasized that although atrophic cells may have diminished function, they are not dead. Mechanisms: Atrophy results from decreased protein synthesis and increased protein degradation in cells. Protein synthesis decreases because of reduced metabolic activity. Example: o Physiologic atrophy is common during normal development (notochord and thyroglossal duct). o Pathologic atrophy depends on the underlying cause: Decreased workload (atrophy of disease) bedrest/plaster cast on fractures bones Loss of innervation (denervation atrophy) atrophy of muscle fibers because of nerve damage Diminished blood supply ischemia to a tissue may result in atrophy e.g. brain may undergo progressive atrophy because of ischemia by atherosclerosis Inadequate nutrition in marasmus Loss of endocrine stimulation e.g. loss of estrogen after menopause Pressure tissue compression for any length of time can cause atrophy

C. HYPERPLASIA
Hyperplasia is an adaptive response in cells capable of replication and usually resulting in increased mass of tissue or organ. Occurs in tissue whose cell are able to divide. Pathologic hyperplasia constitutes a fertile soil for cancer proliferation. Hyperplasia can be physiologic or pathologic. Physiologic hyperplasia: o Hormonal hyperplasia: increases the functional capacity of a tissue when needed e.g. proliferation of glandular epithelium of female breast at puberty and during pregnancy accompanied by hypertrophy of glandular epithelial cells. o Compensatory hyperplasia: increases tissue mass after

damages/partial resection e.g. donating one lobe of liver remaining cells proliferate so the organ soon grows back to its original size. Pathologic hyperplasia: caused by excess of hormones/growth factors acting on target cells. For example: o Disturbance of balance between estrogen and progesterone increase in amount of estrogen hyperplasia of endometrial gland (abnormal menstrual bleeding) o Hyperplasia is also an important response of connective tissue cells in wound healing, in which proliferating fibroblasts and blood vessels aid in repair.

D. METAPLASIA
Metaplasia is a reversible change in which one differentiated cell type (epithelial or mesenchymal) is replaced by another cell type, which is better able to withstand the adverse environment. The influences that predispose to metaplasia, if persistent, may initiate malignant transformation of metaplastic epithelium. Example:

o The normal ciliated columnar epithelial cells of the trachea and bronchi are widely replaced by stratified squamous epithelial cells (in cigarette smokers). o Vitamin A deficiency may also induce squamous metaplasia in the respiratory epithelium. o In chronic gastric reflux, the normal stratified squamous epithelium of the lower esophagus may undergo metaplastic transformation to gastric or intestinal-type columnar epithelium.

CELL INJURY AND CELL DEATH

A. CELL INJURY

Cell injury results when cells are stressed so severely that they are no longer able to adapt or when cells are exposed to inherently damaging agents or suffer from abnormalities. Injury may progress through a reversible stage and irreversible stage. intrinsic

TYPE OF CELL INJURY

1. Reversible Injury Occur in early stages or mild forms of injury. The functional and morphologic changes are reversible if the damaging stimulus is removed.

The hallmarks of reversible injury : a. Reduced oxidative phosphorylation with resultant depletion of energy stores in the form of adenosine triphosphate (ATP)

b. Cellular swelling caused by changes in ion concentrations and water influx c. In addition, various intracellular organelles, such as mitochondria and the cytoskeleton, may also show alterations

2. Irreversible Injury With continuing damage the injury becomes irreversible, at which time the cell cannot recover and it dies (undergo cell death).

CAUSE OF CELL INJURY a. Loss of blood supply or loss of oxygen-carrying capacity Oxygen deprivationreducing aerobic oxidative respiration b. Physical agents : mechanical trauma, temperature, radiation, electric shock c. Chemical agents : Imbalanced concentration, poison d. Environment & air pollutant : social stimuli (alcohol & narcotics) e. Infectious agents : virus, worms, bacteria, fungi f. Immunologic reactions g. Genetic derangement : Chromosomal abnormality, point mutation h. Nutritional imbalances : deficiency and excess

MECHANISM OF CELL INJURY Principle: 1. Depends on the type, duration, and severity of the injury 2. Depends on the type, state, and adaptability of cell 3. Results from functional and biomechanical abnormality

B. CELL DEATH
Cell death occurs when the injury becomes irreversible due to continued damage, at which time the cell cannot recover and it dies. Cell death is divided into two morphologic and mechanism pattern, necrosis and apoptosis. There are 2 principles of cell death: a. Necrosis When damage to membranes is severe, lysosomal enzymes enter the cytoplasm and digest the cell, and cellular contents leak out. b. Apoptosis When the cell' s DNA or proteins are damaged beyond repair, the cell kill itself. A form of cell death that is characterized by nuclear dissolution, fragmentation of the cell without complete loss of membrane integrity, and rapid removal of the cellular debris.

Features of Necrosis and Apoptosis

Pyknosis : degenerasi sel dimana ukuran sel mengecil dan kromatin mengalami kondensasi menjadi massa yang padat serta tidak berbentuk Karyorrhexis : pecahnya inti sel dimana kromatinnya hancur menjadi granul-granul yang tidak berbentuk, yang dikeluarkan dari sel.

Karyolysis : Terputusnya inti sel

INFLAMMATION
Inflammation is a complex reaction in tissues that consists mainly of responses of blood vessels and leukocytes. Inflammation may be acute or chronic, depending on the nature of the stimulus and the effectiveness of the initial reaction in eliminating the stimulus or the damaged tissues.

Physiological Response Local Manifestation Release of soluble mediators Vasodilation Increased blood flow Extravasation of fluid ( permeability) Cellular influx (chemotaxis) Elevated cellular metabolism Heat (Calor) Redness (Rubor) Swelling (Tumor) Pain (Dolor)

A. ACUTE INFLAMMATION
Involves : Hemodynamic changes Exudate formation Presence of granular leukocytes

Local Manifestations Heat (calor) Redness (rubor) Swelling ( tumor) Pain (dolor) Loss Function (functio lesa)

Sistemic Manifestations Fever Chills Malaise Myalgia

Stage of Acute Inflammation 1. Vasodilation 2. Increased vascular permeability 3. Movement of white blood cells (chemotaxis) Process by which white blood cells are drawn to the site of inflammation. The process include : 1) Margination and Rolling Margination: blood leukocytes, predominantly neutrophils, accumulation at the periphery of vessels [cytokines: tumor necrosis factor (TNF), interleukin-1 (IL-1), chemokines] Rolling: the leukocytes adhere transiently to the endothelium, detach and bind again, thus rolling on the vessel's wall. [selectins: L-selectin, E-selectin, P-selectin] 2) Adhesion Rolling leukocytes are able to sense changes in the endothelium that initiate the next step in the reaction of the leukocytes. The cells finally come to rest at some points where they adhere firmly. [integrins]; [other mediators: histamine, thrombin, and platelet-activating factor (PAF)] 3) Diapedesis or transmigration Migration of leukocytes through the endothelium, squeezing between cells at intercellular junction [chemokines] expressed on leukocyte and endothelial cells, mediates the binding event needed for leukocytes to traverse the endothelium enable to pass through the vascular basement membrane leukocyte secrete collagenase PECAM - 1 4) Chemotaxis Movement of leukocytes toward sites of infection or injury along a chemical gradients. Both exogenous and endogenous substances can be chemotactic for leukocytes, including : (1) bacterial products (2) cytokine, especially chemokine family [cytokines, C5a, leukotriene B4].

4. Phagocytosis

Involves three steps: a. Recognition & binding. Microorganism coated by opsonin that enhance phagocytosis efficiency by binding leukocyte receptors. b. Engulfment by encircling pseudopods and enclosure of the particle within an intracellular phagosome c. Killing & degradation of phagocytosed particles 5. Termination Development of inflammation process also trigger stop signal that actively terminate the reaction.

Morphology of Acute Inflammation a. Serous Inflammation Clear, watery fluid appearance. Seen in viral infection and burns. b. Fibrinous Inflammation Finely particulate, thick fluid appearance. Seen in uremic and postmyocardial infarct pericarditis. c. Purulent Inflammation Pus appearance. Seen in bacterial and fungal infection.

B. CHRONIC INFLAMMATION
Chronic inflammation is prolonged process (weeks, months, even years). Involve : Presence of nongranular leukocytes Results in more extensive scarring

Local Manifestations Heat (calor) Redness (rubor) Swelling ( tumor) Pain (dolor) Loss of Function

DIFFERENCES BETWEEN ACUTE AND CHRONIC INFLAMMATION

STIMULI OF INFLAMMATION :

TISSUE HEALING AND TISSUE REPAIR

Injury to cells and tissue sets in motion a series of event that contain the damage and initiate the healing process, it can be separated into:

1. Regeneration Proliferation of cells and tissues to replace lost structure. Type of regeneration depends on tissue type : A. LABILE Capable of lifelong regeneration B. STABLE Tissue can regenerate when stimulated C. PERMANENT No regenerative ability 2. Repair Combination of regeneration and scar formation by deposition of collagen. 3. Healing A process of cure, restoration of integrity to injured tissue. I. First Intention A. Minimal Tissue Loss B. No Granulation Formation II. Second Intention A. Significant Tissue Loss B. Granulation Tissue C. Slow Healing D. Scar Tissue Healing is repair involving a combination of regeneration and connective tissue deposition. Scarring occurs when tissues are intrinsically unable to regenerate. Regeneration is cell or tissue growth that replaces lost structures

STEM CELLS
Characterized by prolonged self renewal capacity and by asymmetric replication Embryonic stem cells capable to differentiate into any tissue type The functions are: To identify signals required for normal tissue differentiation To generate animals congenitally deficient in specific genes by inactivating or deleting gene in embryonic stem cells (ES) then incorporating the modified ES to a developing blastocyst Potentially of use in repopulating damaged organ Stem cell can also come from adult tissue, the example is bone marrow that contains hematopoietic stemm cells. Adult stem cells are numbers of reservoir cells in normal adult tissues located in niches unique to each tissue.Ex: Bone marrow contain hematopoietic stem cells (HSCs) Mesodermal lineage cells are capable of differentiating into neuron, hepatocytes Fuse with host cells, transfering genetic material and giving the false impression of transdifferentiation Multipotent adult progenitor cells which are have broad developmental capacity The role of stem cell in tissue homeostatis are: Epithelium; most epithelial surfaces are constantly maintained by stem cells with a discrete set of differentiation lineages. After injury stem cells can repopulate the tissue Liver; liver stem cells reside in the canals of Hering with capacity to form hepatocytes or biliary epithelium Brain; neural stem cells exist and can even be integrated into neural circuit

GROWTH FACTORS
Function: Stimulating proliferating Affect cells movement, contractility, differentiation, angiogenesis Major growth factors are : EGF (Epidermal Growth Factor), TGF- (Transforming Growth Factor) HGF (Hepatocytes Growth Factor) is produced by fibroblast, endothelial cells and hepatocytes VEGF (Vascular Endothelial Growth Factor) play role in vasculogenesis and angiogenesis PDGF (Platelet-derived Growth Factor) FGFs (Fibroblast Growth Factors) TGF- is a growth inhibitor for most epithelial cells and has potent anti inflammatory effects

SIGNALING MECHANISM IN CELL GROWTH

Autocrine: cells respond to signaling substances produced by themselves Paracrine: a cell produce substances that affect target cells in close proximity Endocrine: cells synthesize hormones that circulate in the blood to act on distant targets

MECHANISM OF TISSUE REGENERATION

Mammals lack this capacity & regeneration in damaged tissues is largely just compensatory growth involving cell hypertrophy ad hyperplasia. This will restore the functional capacity but doesnt reconstitute the original anatomy. This ascribed to a rapid fibropoliferative response and scar formation after wounding.

REGENERATION, HEALING AND FIBROSIS

The main healing process is repair by deposition of collagen and other ECM components, causing the formation of a scar. Repair by connective tisue deposition includes: Inflammation Angiogenesis (blood vessel formation in adults) Migration and proliferation of fibroblast Scar formation Connective tissue remodelling

Mechanism of Angiogenesis From Preexisting Vessels Vasodilation in response to nitric oxide and VEGF-induced increased permeability of vessels

Proteolytic degradation of basement membrane of parent vessel by MMPs

Disruption of cell to cell contact between endothelial cells by plasminogen activators

Migration of endothelial cell towards the angiogenic stimulus Proliferation of endothelial cells behind the leading front of migrating cells

Maturation of endothelial cells (inhibition of growth) Recruitment of periendothelial cells (vascular smooth muscle cells to form the mature vessels)

From Endothelial Percusor Cells (EPC) EPCs can be recruited from the bone marrow into tissues Migrate to a site of injury or tumor growth EPCs differentiate and form a mature network by linking to existing vessels. EPCs express some markers of hematopoietic stem cells as well as VEGR-2 and VE-catherin. The growth factor and receptor in angiogenesis are VEGF (vascular endothelial growth factor), and bFGF(base fibroblast growth factor)

Regulator of Angiogenesis: ECM proteins Integrins (V3): for the formation and maintenance of newly formed blood vessels Matricellular proteins (thrombospondin 1, SPARC, tenascin C): destabilize cell-matrix interactin and promote angiogenesis Proteinase (plasminogen activator and MMPs): remodelling during endothelial invasion, cleave extracellular protein, release inhibitor such as endostatin

Cutaneous Wound Healing 1. Inflammation Initial injury causes platelet adhesion and aggegation, blood clotting

2. Proliferation Formation of granulation tissue, proliferation and migration of connective tissue cells, re-epithelization of wound surface 3. Maturation ECM deposition, tissue remodelling, wound contraction Healing by First or Second Intention First intention Minimal tissue loss and no granulation formation Second intention significant tissue loss granulation tissue slow healing scar tissue

Sequence of events 1) Formation of blood clot The clot serves to stop bleeding and also as scaffold for migrating cells Within 24 hours, neutrophils appear at margin of the incision Neutrophils release proteolytic enzymes that clean out debris and invading bacteria 2) Formation of granulation tissue Its characteristic histology feature is the presence of the new small blood vessel (angiogenesis) and the proliferation of fibroblast Fibroblast and vascular endothelial cells proliferate in the first 24-72 hours forming specialized type of tissue called granulation tissue Amount of granulation tissue depends on the size of the tissue deficit and intensity of inflammation By 5-7 days, granulation tissue fills the wound area and

neovascularization is maximal 3) Cell proliferation and collagen deposition Neutrophils are replaced by macrophages by 48-96 hours

 Migration of fibroblast is driven by chemokines, TNF, PDGF, TGF-, and FGF. Their proliferation is triggered by TNF, PDGF, TGF-. FGF, IL-1, and TNF. Macrophages are the main sources of these factors. Collagen fibers are now present at the margins of incision, but at first these are vertically oriented and do not bridge the incision In the 24-48 hours, spours of epithelial cells move from the wound edge along the cut margins of the dermis, depositing basement membrance component as they move. They fuse in the midline beneath the surface scab, producing a thin, continuous epithelial layer that closes the wound 4) Scar formation The leukocytic infiltrate, Edema, and increased vascularity largely disappear during the second week Blanching begins, accomplished by the increased occumulation of collagen within the wound area and regression of vascular channel 5) Wound contraction Generally occur in large surface of wounds The contraction helps to close the wound by decreasing the gap between its dermal edge and by reducing the wounds surface area 6) Connective tissue remodelling The replacement of granulation tissue with a scar involves transitions in the composition of the ECM. Some of the growth factors that stimulate synthesis of collagen and other concetive tissue molecules also modulate the synthesis and activation of metalloproteinase, enzymes that degrade these ECM components The balance between ECM synthesis and degradation results in remodelling of the connective tissue framework-an important feature of both chronic inflammation and wound repair 7) Recovery of tensile strength Scar tissue may achieve may achieve 70-80% of the tensile strength of unwounded skin Result from excess of collagen synthesis over collagen degradation during the first 2 months of healing

Factors Influencing Wound Healing

a. Systemic factor: nutrition, metabolic status, circulatory system, hormone b. Local factor: infection, mechanical factor, foreign bodies, size, location, and type of wound Fibrosis Fibrosis is emigration and proliferation of fibroblast in the site of injury and deposition of ECM in the fibroblast. The proliferation of fibroblast is: i. Migration of fibroblast and their proliferation are triggered by multiple GF ( TGF-, PDGF, EGF, FGF, Fibrogenic cytokines, IL-1, TNF) ii. TGF- : Fibroblast migration and proliferation, increasing of the synthesis of collagen and fibronectin and degradation of ECM Extracellular atrix deposition are: decreasing of fibroblast, increasing of deposit of ECM, synthesis and accumulation of collagen, and collagen synthesis is enhanced by (PDGF, FGF, TGF-) and cytokines (IL-1, IL-4)

EXTRACELLULAR MATRIX & CELL MATRIX INTERACTIONS

ECM is dynamic, constantly remodellingmacromoleculer complex synthesized locally and constituting a significant proportion of any tissue.

ECM supplies a substratum for cell adhesion and critically regulates the growth, movement, and differentiattionof the cells living within it.

ECM occurs in two basic form: 1. Interstitiel matrix 2. Basement membrane

ROLES OF EXTRACELLULAR MATRIX

- Mechanical support for cell anchorage - Determination of cell orientation (polarity) - Control of cell growth - Maintenance of cell differentiation - Scaffolding for tissue renewal - Establishment of tissue microenvironments - Storage and presentation of regulatory molecules

COMPONENTS OF THE EXTRACELLULER MATRIX 1. Collagen and elastin 2. Proteoglycans and hyaluronan 3. Adhesive glycoprotein and integrin

REPAIR BY HEALING, SCAR FORMATION AND FIBROSIS

After injury, tissues may regenerate or heal Regeneration involves restitution of tissue identical to that lost by injury Healing is a fibro proliferative responses that patches rather than restores a tissue For tissue incapable of regeneration, repair is accomplished by ECM deposition, producing a scar.

The Sequence of Healing Inflammatory response to eliminate the initial stimulus, remove injured tissue, initiate ECM deposition Proliferation & migration of parenchymal & connective tissue cells Formation of new blood vessels (angiogenesis) Migration and proliferation of fibroblast Deposition of ECM Maturation and organization of fibrous tissue

HAEMODYNAMIC DISORDER
A. EDEMA
Edema signifies increased fluid in the interstitial tissue spaces. Depending on the site, fluid collections are variously designated hydrothorax, hydropericardium, and hydroperitoneum (ascites).

Types of Edema Transdate - protein poor (<3 gm/dl) fluid with specific gravity of <1.012 due to imbalances in normal hemodynamic forces e.g. congestive heart failure, liver and renal disease etc. Exudate - protein rich (>3 gm/dl) fluid with a specific gravity of >1.020 results from endothelial damage and alteration of vasular permeability e.g. inflammatory and immunologic pathology.

Process of Edema

B. HYPEREMIA & CONGESTION

Hyperemia is an active process resulting from tissue inflow because of arteriolar dilation, e.g. skeletal muscle during exercise or at sites of inflammation. The affected tissue is redder because of the engorgement of vessels with oxygenated blood. Congestion is a passive process resulting from impaired outflow from a tissue. It may be systemic e.g. cardiac failure, or local e.g. an isolated venous obstruction. The tissue has a blue-red color (cyanosis), due to accumulation of deoxygenated hemoglobin in the affected tissues.

C. SHOCK
Shock, or cardiovascular collapse, is the final common pathway for a number of potentially lethal clinical events, including severe hemorrhage, extensive trauma or burns, large myocardial infarction, massive pulmonary embolism, and microbial sepsis.

The type of shock: Cardiogenic shock results from myocardial pump failure e.g intrinsic myocardial infarction, ventricular arrhythmias. Hypovolemic shock results from loss of blood or plasma volume e.g. hemorrhage, fluid loss from severe burns, or trauma. Septic shock is caused by systemic microbial infection. Most commonly due to gram-negative infections (endotoxic shock),but it can also occur with grampositive and fungal infections. Neurogenic shock: anesthetic accident or spinal cord injury can lead to loss of vascular tone and peripheral pooling of blood. Anaphylactic shock: initiated by a generalized IgE-mediated hypersensitivity response, is associated with systemic vasodilation and increased vascular permeability.

MICROSCOPIC FEATURE OF CERTAIN ABNORMALITIES (LAB ACT)

1. 2. 3. 4. Cell Injury Tissue Repair Metaplasia Infectious : : : : Cellular Injury Cirrhosis Cervix Lymphadenitis Tuberculosa Reactive Hyperplasia Of The Lymph Node 5. Inflammation : Acute Appendicitis Chronic Cholecystitis 6. Haemodynamic : Hemorrhoid

Abnormality Cellular Injury

Microscopic Small nuclear vacuoles may be seen within the cytoplasm Represent distended and

pinched-off segments of the ER

Cirrhosis Of The Liver

Diffuse

hepatic

fibrosis

with

replacement of normal nobular architecture by parenchymal

nodules separated by fibrous tissue Portal-central septa linking portal tracts and central vein are the c omponent of cirrosis

Metaplasia

Columnar endocervix

cell is

lining replaced

the by

squamous cells

Lymphadenitis Tuberculosa

The

appearance

range

from

multiple small epitheloid granuloma to huge caseous masses surronded by langerhans giant cells,

epitheloid cells, and lymphocyte

Reactive Hyperplasia

The margins of reactive follicles are sharply defined and

surrounded by a mantle of small lympocites often arranged

circumferencially with onion-skin pattern The follicles are composed of an admixture of small and large lymphoid nuclei cell with irregular

Acute Appendicitis

Acute inflammatory cells are scattered mucosa, throughtout submucosa, the and

muscularis propia. Usually seen in serous layer The abnormality is indicated by PMN Chronic Cholecystitis In mildest cases, only scattered lymphocyte, plasma cell and macrophages.

Hemorrhoid

The lesion consist of thin walled dilated submucosal varices that protude beneath the anl/ rectal mucosa. Thrombosis of these dilated vein is frequent.

IMMUNITY PROCESS

Figure 6-1 Innate and adaptive immunity. The principal mechanisms of innate immunity and adaptive immunity are shown.

A. INNATE IMMUNITY
Innate immunity also called natural or native immunity, refers to defense mechanisms that are present even before infection and have evolved to specifically recognize microbes and protect multicellular organisms against infections. The major components of innate immunity are epithelial barriers that block entry of environmental microbes, phagocytic cells (mainly neutrophils and macrophages), natural killer (NK) cells, and several plasma proteins, including the proteins of the complement system. Phagocytes are recruited to sites of infection, resulting in inflammation, and here the cells ingest the microbes and are then activated to destroy the ingested pathogens. Phagocytes recognize microbes by several membrane receptors.

1. Macrophages

Macrophages are a part of the mononuclear phagocyte system. Macrophages play important roles both in the induction and in the effector phase of immune responses.

2. Dendritic Cells

a. Interdigitating dendritic cells (dendritic cells)

These cells are the most important antigen-presenting cells for initiating primary immune responses against protein antigens . Several features of dendritic cells account for their key role in antigen presentation. First, these cells are located at the right place to capture antigens under epithelia, the common site of entry of microbes and foreign antigens, and in the interstitia of all tissues, where antigens may be produced. Immature dendritic cells within the epidermis are called Langerhans cells. Second, dendritic cells express many receptors for capturing and responding to microbes (and other antigens) , including TLRs and mannose receptors. Third, in response to microbes, dendritic cells express the same chemokine receptor as do naive T cells and are thus recruited to the T-cell zones of lymphoid organs, where they are ideally located to present antigens to recirculating T cells. Fourth, dendritic cells express high levels of MHC class II molecules as well as the costimulatory molecules B7-1 and B7-2. Thus, they possess all the machinery needed for presenting antigens to and activating CD4+ T cells.

b. Follicular dendritic cells

These cells present in the germinal centers of lymphoid follicles in the spleen and lymph nodes.

These cells bear Fc receptors for IgG and receptors for C3b and can trap antigen bound to antibodies or complement proteins . Such cells play a role in ongoing immune responses by presenting antigens to B cells and selecting the B cells that have the highest affinity for the antigen , thus improving the quality of the humoral immune response. Follicular dendritic cells also play a role in the pathogenesis of the acquired immunodeficiency syndrome (AIDS).

3. Natural Killer Cells

NK cells make up approximately 10% to 15% of the peripheral blood lymphocytes and do not bear T-cell receptors or cell surface

immunoglobulins. Morphologically, NK cells are somewhat larger than small lymphocytes, and they contain

abundant azurophilic granules. Hence, they are also called large granular lymphocytes. NK cells are endowed with an innate ability to kill a variety of

tumor cells, virally infected cells, and some normal cells, without previous sensitizat ion. These cells are part of the innate immune system, and they may be the first line of defense against viral infections and, perhaps, some tumors. NK cells do not rearrange T-cell receptor genes and are CD3 negative. Two cell surface molecules, CD16 and CD56, are widely used to identify NK cells. CD16 is the Fc receptor for IgG and it endows NK cells with another function, the ability to lyse IgG-coated target cells. This phenomenon, known as antibody-dependent cell-mediated cytotoxicity. The functional activity of NK cells is regulated by a balance between signals from activating and inhibitory receptors. The activating receptors stimulate NK cell killing by recognizing ill-defined molecules on target cells, some of which may be viral products; the inhibitory receptors inhibit the activation of NK cells by recognition of self-class I MHC molecules. The class I MHC-recognizing inhibitory receptors on NK cells are aptly called killer inhibitory receptors. NK cells also secrete cytokines, such as IFN-, TNF, and granulocyte macrophage colony-stimulating factor (GM-CSF).

B. ADAPTIVE IMMUNITY
Adaptive immunity (also called acquired, or specific, immunity) consists of mechanisms that are stimulated by (adapt to) microbes and are capable of also recognizing nonmicrobial substances, called antigens. Innate immunity is the first line of defense, because it is always ready to prevent and eradicate infections. Adaptive immunity develops later after exposure to microbes and is even more powerful in combating infections. By convention, the term "immune response" refers to adaptive immunity. The adaptive immune system consists of lymphocytes and their products, including antibodies. The receptors of lymphocytes are much more diverse than those of the innate immune system, but lymphocytes are not inherently specific for microbes, and they are capable of recognizing a vast array of foreign substances. In

the remainder of this introductory section we focus on lymphocytes and the reactions of the adaptive immune system.

1. T Lymphocytes

T lymphocytes are generated from immature precursors in the thymus. Mature, naive T cells are found in the blood, where they constitute 60% to 70% of lymphocytes, and in T-cell zones of peripheral lymphoid organs, such as the paracortical areas of lymph nodes and periarteriolar sheaths of the spleen. The segregation of naive T cells to these anatomic sites is because the cells express receptors for chemoattractant cytokines (chemokines) that are produced only in these regions of lymphoid organs. Each T cell is genetically programmed to recognize a specific cell-bound antigen by means of an antigen-specific T-cell receptor (TCR). In approximately 95% of T cells, the TCR consists of a disulfidelinked heterodimer made up of an and a polypeptide chain , each having a variable (antigen-binding) and a constant region. The TCR recognizes peptide antigens that are displayed by major histocompatibility complex (MHC) molecules on the surfaces of antigen-pressenting cells. T cells (in contrast to B cells) cannot be activated by soluble antigens; therefore, presentation of processed, membrane-bound antigens by antigen-presenting cells is required for induction of cell-mediated immunity.

2. B Lymphocytes

B lymphocytes develop from immature precursors in the bone marrow. Mature B cells constitute 10% to 20% of the circulating peripheral lymphocyte population and are also present in peripheral lymphoid tissues such as lymph nodes, spleen, or tonsils and extralymphatic organs such as the gastrointestinal tract. In lymph nodes, they are found in the superficial cortex. In the spleen, they are found in the white pulp. At both sites, they are aggregated in the form of lymphoid follicles, which on activation develop pale-staining germinal centers. B

cells are located in follicles, the B-cell zones of lymphoid organs, because the cells express receptors for a chemokine that is produced in follicles. B cells recognize antigen via the B-cell antigen receptor complex. Immunoglobulin M (IgM) and IgD, present on the surface of all naive B cells, constitute the antigen-binding component of the B-cell receptor complex. As with T cells, each B-cell receptor has unique antigen specificity, derived in part from somatic rearrangements of immunoglobulin genes. After antigenic stimulation, B cells form plasma cells that secrete immunoglobulins, which are the mediators of humoral immunity. In addition to membrane immunoglobulin, the B-cell antigen receptor complex contains a heterodimer of nonpolymorphic transmembrane proteins Ig and Ig. Similar to the CD3 proteins of the TCR, Ig and Ig do not bind antigen but are essential for signal transduction through the antigen receptor. B cells also express several other nonpolymorphic molecules that are essential for B-cell function.

CYTOKINES messenger molecules of the immune system

Many such interactions depend on cell-to-cell contact; however, many interactions and effector functions are mediated by short-acting soluble mediators, called cytokines. This term includes the previously designated lymphokines (lymphocyte-derived), monokines (monocyte-derived), and several other

polypeptides that regulate immunologic, inflammatory, and reparative host responses. Molecularly defined cytokines are called interleukins, implying that they mediate communications between leukocytes. Most cytokines have a wide spectrum of effects, and some are produced by several different cell types.

1. Cytokines that mediate innate (natural) immunity. Included in this group are IL-1, TNF (tumor necrosis factor, also called TNF-), type 1 interferons, and IL-6. Some cytokines, such as IL-12 and IFN-, are involved in both innate and adaptive immunity against intracellular microbes. Certain of these cytokines (e.g., the interferons)

protect against viral infections, whereas others (e.g., IL-1 and TNF) promote leukocyte recruitment and acute inflammatory responses. 2. Cytokines that regulate lymphocyte growth, activation, and

differentiation. Within this category are IL-2, IL-4, IL-12, IL-15, and transforming growth factor- (TGF-). IL-2 is an important growth factor for T-cells, IL-4 stimulates differentiation to the TH2 pathway and acts on B cells as well, IL-12 stimulates differentiation to the TH1 pathway, and IL-15 stimulates the growth and activity of NK cells. Other cytokines in this group, such as IL-10 and TGF-, down-regulate immune responses. 3. Cytokines that activate inflammatory cells In this category are IFN-, which activates macrophages; IL-5, which activates eosinophils; and TNF and lymphotoxin (also called TNF-), which induce acute inflammation by acting on neutrophils and endothelial cells. 4. Cytokines that affect leukocyte movement are also called chemokines The C-X-C chemokines are produced mainly by activated macrophages and tissue cells (e.g., endothelium), whereas the C-C chemokines are produced largely by T cells. Different chemokines recruit different types of leukocytes to sites of inflammation. Chemokines are also normally produced in tissues and are responsible for the anatomic localization of different cell types, for example, the location of T and B cells in distinct regions of lymphoid organs. 5. Cytokines that stimulate hematopoiesis. Many cytokines derived from lymphocytes or stromal cells stimulate the growth and production of new blood cells by acting on hematopoietic progenitor cells. Several members of this family are called colonystimulating factors (CSFs) because they were initially detected by their ability to promote the in vitro growth of hematopoietic cell colonies from the bone marrow. Some members of this group (e.g., GM-CSF and G-CSF) act on committed progenitor cells, whereas others, exemplified by stem cell factor (c-kit ligand), act on pluripotent stem cells.

INFECTIOUS DISEASE
CATEGORIES OF INFECTIOUS AGENTS

BACTERIAL INFECTION

Optional: untuk SOOCA saja.

ROUTES OF ENTRY, DISSEMINATION, AND RELEASE OF MICROBES FROM THE BODY

HOW MICROORGANISMS CAUSE DISEASE

Infectious agents establish infection and damage tissues in three ways:

They can contact or enter host cells and directly cause cell death. They may release toxins that kill cells at a distance, release enzymes that degrade tissue components, or damage blood vessels and cause ischemic necrosis. They can induce host cellular responses that, although directed against the invader, cause additional tissue damage, usually by immune-mediated mechanisms. Thus, as we

The defensive responses of the host are a two-edged sword: They are necessary to overcome the infection but at the same time may directly contribute to tissue damage.

Pada kasus ini, bakteri yang terlibat adalah Staphylococcus aureous yang merupakan bakteri aerob. Sebenarnya, bakteri ini banyak terdapat di permukaan kulit (ini adalah hal yang normal). Tetapi, apabila terjadi luka pada kulit, maka bakteri tersebut akan masuk ke dalam kulit sehingga menyebabkan infeksi dan dapat menyebabkan carbuncle.

The final common pathway of many infections is chronic inflammation, which can lead to extensive scarring.

BHP
Doctor should give complete information with right attitude Respect for patients privacy (confidentiality) Ask for permition to do physical examination (gluteal region) Informed consent about culture examination Giving right antibiotic type and dosage then give explanation about drugs administration Follow up the patient Explain to patient the scra that will be formed

PHOP
Educate the patients about healthy life (personal hygiene) Education about carbuncle Education about environment sanitary Explain about control of communicable disease