DISEASES OF IMMUNITY

The Immune System

IMMUNITY- refers to protection against infections, and the immune system is the collection of cells and molecules that are responsible for defending us against the countless pathogenic microbes in our environment . Usually works effectively but illness may result from inadequate immune activity excessive immune activity inappropriate immune activity

antigen
is a substance or molecule that, when introduced into the body, triggers the production of an antibody by the immune system, which will then kill or neutralize the antigen that is recognized as a foreign and potentially harmful invader.

antibody
antibody, also known as an immunoglobulin, is a large Yshaped protein used by the immune system to identify and neutralize foreign objects such as bacteria and viruses. The antibody recognizes a unique part of the foreign target, termed an antigen

TYPES OF IMMUNE REACTIONS

Innate immunity (natural, or native immunity)-mediated by cells and proteins that are always present and poised to fight against microbes and are called into action immediately in response to infection . major components of innate immunity are 1. epithelial barriers of the skin, gastrointestinal tract, and respiratory tract, which prevent microbe entry (and have to be breached for a microbe to establish infection); 2. phagocytic leukocytes (neutrophils and macrophages); 3. a specialized cell type called the natural killer (NK) cell; and 4. several circulating plasma proteins, the most important of which are the proteins of the complement system

TYPES OF IMMUNE REACTIONS

adaptive immunity (acquired, or specific immunity)-is normally silent and responds (or "adapts") to the presence of infectious microbes by becoming active, expanding, and generating potent mechanisms for neutralizing and eliminating the microbes. The components of the adaptive immune system are lymphocytes and their products two types of adaptive immune responses: 1. humoral immunity, mediated by soluble antibody proteins that are produced by B lymphocytes (also called B cells), 2. cell-mediated (or cellular) immunity, mediated by T lymphocytes (also called T cells)

CELLS AND TISSUES OF THE IMMUNE SYSTEM

 B lymphocytes participate in immunity either by directly neutralizing extracellular microbes or by activating complement & effector cells ( neutrophils & macrophages) to kill microorganism comprise 10% to 20% of the circulating peripheral lymphocyte population Present in bone marrow, in peripheral lymphoid tissues (lymph nodes, spleen & tonsils) & in GIT after stimulation,form plasma cells that secrete immunoglobulins which are the mediators of humoral immunity Five basic immunoglobulin isotypes: IgG, IgM, and IgA constitute more than 95% of circulating antibodies IgE and IgD

B lymphocytes

 IgA is an important mediator of mucosal immunity IgE important for helminth infections ( and in allergic response) T lymphocytes ( T cells) can either directly lyse targets (accomplished by cytotoxic T cells) or orchestrate the antimicrobial immune response of other cells by producing soluble protein mediators called cytokines (made by helper T cells) constitute 60% to 70% of the lymphocytes in circulating blood present in splenic periarteriolar sheaths & lymph node interfollicular zones

T lymphocytes ( T cells)

 Macrophages

Phagocytose (and ultimately kill) microbes coated by antibody and/or complement (opsonized) important effector elements in humoral immunity produces cytokines Dendritic cells Cells with dendritic morphology (with fine dendritic cytoplasmic processes) occur as two types Interdigitating dendritic cells occur in lymphoid tissues & in the interstitium of the heart & lungs Follicular dendritic cells located in the germinal centers of lymphoid follicles in the spleen & lymph nodes

Macrophage

Dendritic cells

Natural Killer (NK) Cells comprise 10% to 15% of peripheral blood lymphocytes contain azurophilic granules & are able to lyse a variety of tumor cells, virally infected cells & some normal cells Classified as part of the innate immune system Features of Humoral and ImmunityImmunity Immunity Humoral Cellular Cellular

Principal Cells Assisting cells

B cell lymphocytes Macrophages

T cell lymphocytes Macrophages T helper cells Lymphokines Cytotoxic cells Viruses, fungi, transplants, tumor cells

End result Effective against

Immunoglobulin Bacteria ,toxins

Natural Killer (NK) Cells

HYPERSENSITIVITY REACTIONS Implies abnormal or excessive sensitivity to an antigen May result from a perfectly normal immune response to an antigen ( e.g. the rejection of tissue grafts from antigenically dissimilar donors) Classified on the basis of the immunologic mechanism initiating the disease Subdivision of hypersensitivity reactions Type I disease results from IgE antibodies adsorbed on mast cells or basophils Type II disorders are caused by humoral antibodies that bind to fixed tissue or cell surface antigen & cause a pathologic process by predisposing cells to phagocytosis or to lysis Type III disorders are called immune complex diseases antibodies bind antigens to form large antigen-antibody complexes that precipitate in various vascular beds

 Type IV disorders (also called delayed-type hypersensitivity) are cell-mediated immune responses where antigen-specific T lymphocytes are the ultimate cause of the cellular & tissue injury Mechanisms of Immunologically Mediated Disorder Type I Hypersensitivity (Allergy and Anaphylaxis) A tissue response that occurs rapidly (within minutes) after the interaction of allergen with IgE antibody previously bound to the surface of mast cells basophils in a sensitized host Prototype Disorder Anaphylaxis, some forms of bronchial asthma Other examples: local reaction like seasonal rhinitis or hay fever

 Two well-defined phases of localized type I reactions initial response, characterized by vasodilation, vascular leakage & smooth muscle spasm usually evident within 5 to 30 minutes after exposure to an allergen & subsiding by 60 minutes second, late-phase reaction that sets in 2 to 8 hours later & lasts for several days Mast cells & basophils are central to the development of Type I hypersensitivity

basophils Mast cells

CLINICAL MANIFESTATIONS May occur as a systemic disorder or as a local reaction Systemic anaphylaxis results from systemic (parenteral) administration of protein antigens or drugs (e.g. bee venom or penicillin) Signs & symptoms in a sensitized host 1.Itching, urticaria (hives), & skin erythema 2. Respiratory difficulty ( caused by pulmonary broncho constriction accentuated by hypersecretion of mucus 3. Upper airway obstruction due to laryngeal edema 4. Vomiting, abdomial cramps, and diarrhea ( GIT musculature) Without immediate intervention the ff. may result 5. Anaphylactic shock (systemic vasodilation) 6. Circulatory collapse & death within minutes

 Local reactions occur when the antigen is confined to a particular site by virtue of the route exposure, such as skin (contact, causing urticaria) GIT (ingestiion, causing diarrhea), Lung (inhalation, causing bronchoconstriction) Common forms of skin & food allergies, hay fever and certain forms of asthma are examples of localized anaphylactic reactions Atopy is used to imply familial predisposition to localized type I reactions Patients who suffer from bronchial allergy (including hay fever & asthma) often have a history of similar conditions Type I hypersensitivity plays an important role in parasitic infections IgE antibodies are produced in response to many helminthic infections

Pathogenesis - Atopic Asthma

Mechanism of Asthma Allergy Inflammation Of Bronchi Obstruction by Mucus Plugs

INFLAMMATION

INDUCERS Allergens, pollutants

Airway Hyperresponsiveness Genetic*

Airflow Limitation

,
TRIGGERS Exercise Cold Air, diseases,

Epidemiology/pathology

Normal

Asthma

Barnes PJ

Lung in Asthma with Mucous plugs

Mucous plug in asthma

Mucous plugs contain whorls of shed epithelium (Curschmann Spirals), eosinophils & Charcot-Leyden crystals (collection of Crystalloids made up of eosinophil proteins

Asthma Microscopic Pathology

Obstructed Inflammed Bronchi

 Type II Hypersensitivity (Antibody Dependent) Mediated by antibodies directed against target antigens on the surface of cells or other tissue components The antigens may be normal molecules intrinsic to cell membranes or extracellular matrix This occurs in the following situation Transfusion reactions red cells from an incompatible donor are destroyed after being coated with recipient antibodies directed against the donors blood group antigens Erythroblastosis fetalis due to rhesus antigen incompatibility; Autoimmune hemolytic anemia, agranulocytosis or thrombocytopenia resulting from an individuals generating antibodies to his or her own blood cells

 Drug reactions where antibody is directed against a particular drug that is nonspecifically adsorbed to a cell surface ( Ex. Is the hemolysis that can occur after penicillin administration) Pemphigus vulgaris caused by antibodies against desmosomal proteins that lead to disruption of epidermal intercellular junctions Type III Hypersensitivity ( Immune Complex-Mediated) Mediated by the deposition of antigen-antibody (immune) complexes, followed by complement activation & accumulation of polymorphonuclear leukocytes Immune complexes can involve exogenous antigens such as bacteria & viruses or endogenous antigens such as DNA Prototype disorder- Arthus reaction, serum sickness, systemic lupus erythematosus, certain forms of acute glomerulonephritis

 Pathogenesis of systemic immune complex disease can be divided into three phases: 1. formation of antigen-antibody complexes in the circulation 2. deposition of the immune complexes in various tissues, thus initiating 3. an inflammatory reaction in various sites throughout the body Arthus reaction a localized area of tissue necrosis resulting from acute immune complex vasculitis

Type IV Hypersensitivity (Cell-Mediated) This is mediated by specifically sensitized T cells rather than antibodies & is subdivided into two basic types 1) delayed-type hypersensitivity, initiated by CD4 (cluster of differentiation)+ T cells 2) direct cell cytotoxicity, mediated by CD8+ t cells Cell mediated immunity is the principal mechanism of response to a variety of microbes, including intracellular pathogens like Mycobacterium tuberculosis and viruses, as well as extracellular agents such as fungi, protozoa and parasites

cluster of differentiation

Transplant Rejection A complex immunologic phenomenon involving both celland antibody mediated hypersensitivity responses of the host directed against histocompatibility molecules on the donor allograft Classification of rejection reactions Hyperacute rejection occurs within minutes to a few hours after transplantation in a presensitized host. A hyperacutely rejecting kidney rapidly becomes cyanotic, mottled, & flaccid & may excrete only a few drops of bloody fluid Acute rejection may occur within days to weeks of transplantation in a non-immunosupressed host Chronic rejection clinically present late after transplantation (months to years) with a progressive rise in serum creatinine levels over a period of 4 to 6 months

AUTOIMMUNE DISEASES Systemic Lupus Erythematosus An autoimmune, multisystem disease of protean manifestations and variable behavior Clinically it is an unpredictable, remitting, relapsing disease of acute or insidious onset that may involve any organ of the body It principally affects the skin, kidneys, serosal membranes, joints and heart Immunologically, the disease involves an array of autoantibodies, including antinuclear antibodies (ANA) Its prevalence may be as high as 1 case per 2500 persons There is a strong female preponderance affecting 1 in 700 women in child-bearing age More common & severe in black Americans affecting 1 in 245 women in the group Usual onset is in the second or third decade of life but may manifest at any age

Etiology and Pathogenesis The fundamental defect in SLE is a failure to maintain selftolerance Self- tolerance refers to a lack of immune responsiveness to ones own tissue antigens Origin is multifactorial (including genetic, hormonal and environmental factors) resulting in a T- & B-cell activation that culminates in the production of several species of autoantibodies Environmental factors drugs like procainamide and hydrazaline when given for more than 6 months develop ANA Sex hormones Exposure to ultraviolet light

 Diagnosis of SLE is established if a patient demonstrates four or more of the diagnostic criteria Criterion Malar rash Discoid rash Photosensitivity Oral ulcers Arthritis Definition Fixed erythema, flat or raised, over the malar eminences & the bidge of the nose, (butterfly pattern) Erythematous raised patches with adherent keratotic scaling & follicular plugging Rash as a result of unusual reaction to sunlight Oral or nasopharyngeal ulceration, usually painless Involves 2 or more peripheral joints characterized by tenderness, swelling or effusion

Criterion Serositis Renal disorder

Definition Pleuritis & Pericarditis Persistent proteinuria or Cellular casts may be red blood cell,

hemoglobin (lupus nephritis) Neurological disorder Seizures in the absence of an offending drug or metabolic derangements (e.g. uremia or electrolyte imbalance) Hematological disorder Hemolytic anemia or Leukopenia Thrombocytopenia in the absence of offending drugs Immunologic disorder Anti-DNA antibody Antinuclear antibody

LUPUS ERYTHEMATOSUS A. BUTTERFLY LESION IN THE FACE B. PERIARTERIOLAR FIBROSIS-SPLEEN

LUPUS NEPHRITISWIRE LOOPS

 The course of SLE is variable. Some patients have only skin manifestations and/or mild hematuria It is characterized by remissions & relapses spanning years to decades Acute flare-ups are controlled by steroids or other immunosupressive drugs With current therapies 90% 5-year and 80% 10-year survival can be expected Renal failure, intercurrent infections & diffuse CNS involvement are the major causes of death

Rheumatoid Arthritis A systemic, chronic inflammatory disease affecting multiple tissues but principally attacking the joints to produce a nonsuppurative proliferative synovitis that frequently progresses to destroy articular cartilage and underlying bone with resulting disabling arthritis Destroyed articular cartilage is replaced by chronic inflammatory pannus. Has a prevalence of approximately 1% Three to five times more common in women than in men Peak incidence second to fourth decades of life but no age is immune There is genetic predisposition, although the cause or causes of this disease remain unknown. Characterized by the presence of a circulating autoantibody called rheumatoid factor. ( circulating IgM that binds IgG)

Clinical Course Arthritis first appears with aching & stiffness of joints particularly in the morning As the disease advances, the joints become enlarged, motion is limited & ankylosis may appear Vasculitic involvement of the extremities may give rise to Raynaud phenomenon & chronic leg ulcers Helpful in making correct diagnosis are: sterile, turbid synovial fluid with decreased viscocity, poor mucin clot formation & inclusion-breaking neutrophils

Juvenile Rheumatoid Arthritis refers to chronic idiopathic arthritis that occurs in children not a single disease but a heterogeneous group of disorders most of which differ from the adult form of RA except for the destructive nature of the arthritis Uveitis may be present Systemic manifestations are leukocytosis, hepatosplenomegaly, lymphadenopathy & rash Uveitis specifically refers to inflammation of the middle layer of the eye

Seronegative Spondyloarthropathies Characteristic Features Pathologic changes begin in the ligamentous attachments to bone rather than in the synovium Involvement of the sacroiliac joints plus/minus arthritis in other peripheral joints Absence of Rheumatoid Factors (hence the name seronegative spondyloarthropathies ( joint disease of the vertebral column) Association with HLA-B27 Clinical subsets Ankylosing spondylitis Psoriatic arthritis Spondylitis associated with bowel movement Sacroiliitis is a common manifestation

Seronegative Spondyloarthropathies

SJGREN SYNDROME A clinicopathologic entity characterized by dry eyes (keratoconjunctivitis sicca) and dry mouth (xerostomia) resulting from immune-mediated destruction of the lacrimal & salivary glands Occurs as an isolated disorder (primary form) also known as the sicca syndrome or more often in association with another autoimmune disease (secondary form) Reumatoid Arthritis is the most common associated disorder Other associated disorder- SLE, polymyositis, systemic sclerosis, vasculitis or thyroiditis Etiology & Pathogenesis Ductal epithelial cells of the exocrine glands are the primary target systemic B-cell hyperactivity Genetic factors

Clinical Course 90% of cases occur in women between 35 and 45 years old Patients present with dry mouth, lack of tears Salivary glands are often enlarged owing to lymphocytic infiltrates Extraglandular manifestations include synovitis, pulmonary fibrosis & peripheral neuropathy 60% of patients may have an accompanying autoimmune disorder such as RA Increased risk of developing a non-Hodgkin B-cell lymphoma

SJGREN SYNDROME

Dry mouth

Systemic Sclerosis (Scleroderma) Characterized by excessive fibrosis throughout the body & not just the skin Presenting symptom is cutaneous involvement that appears in 95% of cases Visceral involvement - of the GIT, lungs, kidneys, heart and skeletal muscles produces major morbidity and mortality Occurs in the third to fifth decades with the peak incidence in the 50- to 60-year age group Affects women three times more often than men Classification 1. Diffuse scleroderma, characterized by initial widespread skin involvement with rapid progression & early visceral involvement

2. Limited scleroderma, has minimal skin involvement , often confined to the fingers & face. Involvement of the viscera occurs late hence the disease has a benign course. This is also called the CREST syndrome because of its frequent features of Calcinosis, Raynaud phenomenon, Esophageal dysmotility, Sclerodactyly & Teleangiectasia Etiology and Pathogenesis Fibroblast activation with excessive fibrosis is the hallmark of SS Cause is unknown although it is attributed to abnormal activation of the immune system and microvascular injury & not to any intrinsic defect in fibroblast or in collagen synthesis

Systemic Sclerosis (Scleroderma)

Clinical Course Almost all patients develop Raynaud phenomenon A vascular disorder characterized by reversible vasospasm of the arteries Typically the hands turn white on exposure to cold, reflecting vasospasm, followed by a blue color as capillaries & venules dilate & blood stagnates finally the color changes to red as reactive vasodilation occurs Progressive collagenization of the skin leads to atrophy of the hands with increasing stiffness & eventually incomplete immobilization of the joints Difficulty in swallowing results from esophageal fibrosis & resultant hypomotility. Destruction of the esophageal wall leads to atony & dilation Dyspnea & chronic cough reflect pulmonary changes

Raynaud phenomenon

IMMUNODEFICIENCY DISEASES Occur when a part of the immune system is not present or is not working properly May be caused by inherited defects affecting immune system development (Primary Immunodeficiences) secondary effects of other diseases like infection, malnutrition, aging, immunosupression, autoimmunity or chemotherapy (Secondary or acquired immunodeficiences) Primary immunodeficiences X-linked Agammaglobulinemia: Bruton Disease characterized by the failure of pre-B cells to differentiate into B cells; as a consequence there is a resultant absence of gamma globulin in the blood

 Bruton disease becomes apparent approximately about 6 months of age when maternal immunoglobulins are depleted Recurrent bacterial infections such as acute & chronic pharyngitis, sinusitis, otitis media, bronchitis & pneumonia suggest an underlying immune defect Causal organisms are those bacteria pathogens that are cleared by antibody opsonization e.g. Haemophilus influenzae Streptococcus pneumoniae, Staphylococcus aureus IgA Immunodeficiency Most common of all the primary immunodeficiency diseases Affects about 1 in 700 white individuals

 IgA is the major immunoglobulin in mucosal secretion & is involved in airway & GIT defense Predisposes patients to recurrent sinopulmonary infections & diarrhea Thymic Hypoplasia: DiGeorge Syndrome Results from a congenital defect in thymic development with deficient T-cell maturation T cells are absent in the lymph nodes, spleen & peripheral blood Infants with this defect are extremely vulnerable to viral, fungal & protozoal infections This disorder is a consequence of a developmental malformation affecting the third & fourth pharyngeal pouches structures that give rise to thymus, parathyroid glands & portions of the face Treatment is by transplantation of thymic tissue

DiGeorge Syndrome

 Severe Combined Immunodeficiency (SCID) Represents a constellation of genetically distinct syndromes all exhibiting defects in both humoral & cellmediated immune responses A serious immune system disorder that occurs because of a lack of both B and T lymphocytes, which makes it impossible to fight infections Affected infants are susceptible to severe recurrent infections by bacteria, viruses, fungi & protozoans; infections by Candida, Pneumocystis, cytomegalovirus & Pseudomonas may also cause serious disease Also known as the bubble boy disease after a Texas boy with SCID who lived in a germ-free plastic bubble Current treatment is by bone marrow transplantation

Secondary Immunodeficiencies May be encountered in patients with malnutrition, infection, cancer, renal disease or sarcoidosis Occur in patients receiving chemotherapy or radiation therapy for malignancy or immunosuppresive drugs to prevent graft rejection or treat autoimmune diseases Can be caused by loss of immunoglobulins (as in proteinuric renal diseases), inadequate immunoglobulin synthesis (as in malnutrition), or lymphocyte depletion (from drugs or severe infections) These are more common than the disorders of primary genetic origin

Acquired Immunodeficiency Syndrome (AIDS) A retroviral disease caused by the human immunodeficiency virus (HIV) and is characterized by profound immunosuppression leading to opportunistic infections, secondary neoplasms and neurologic manifestations 22 million people have died since it was recognized 20 years ago On the basis of serologic data, an estimated 35 million people (roughly 1 in every 100) globally are infected with HIV 1.4 million children and 17 million women 95% of worldwide HIV infections are in developing countries with Africa carrying 50% of the burden The most rapid increase in HIV infections are in Southeast Asian countries including Thailand, India & Indonesia. It represents the fifth most common cause of death in adults between the ages 25 and 44

Epidemiology Transmission of HIV occurs under conditions that facilitate the exchange of blood or body fluids that contain the virus or virus-infected cells Three major routes Sexual contact Parenteral inoculation Passage of the virus from infected mothers to their newborns Five Groups at Risk for Developing AIDS 1. Homosexual or bisexual males constitute the largest group of infected individuals 2. Intravenous drug abusers with no history of homosexuality 3. Recipients of blood & blood components (but not hemophiliacs) who received transfusions of HIVinfected whole blood or components

4. Hemophiliacs 5. Heterosexual contacts of members of other high- risk groups (chiefly intravenous drug abusers) Epidemiology of HIV infection & AIDS in children 1% of all AIDS cases occur in children About 90% result from transmission of virus from mother to infant 10% of children with AIDS are hemophiliacs Sexual Transmission Predominant mode of infection worldwide In the US, ST HIV cases are due to homosexual or bisexual male contacts but globally are due to heterosexual activity Virus is present in the semen & enters the recipients body through tears or abrasions in mucosa

 All forms of sexual transmission are aided & abetted by the presence of STD that cause genital ulcerations HIV is present in vaginal & cervical cells of infected women & can be spread from female to male about 8fold less efficiently Parenteral Transmission This is well documented in three different groups: 1. Intravenous drug abusers (the largest group) transmission occurs through shared needles, syringes or other paraphernalia contaminated with HIV-containing blood 1. Hemophiliacs receiving factor VIII or IX concentrates 2. Random recipients of blood transfusion

Four measures that must be observed to prevent transmission of HIV by blood transfusion 1. Screening of donated blood & plasma for antibody to HIV 2. Screening for HIV-associated p24 antigen (detectable before the development of humoral antibodies) 3. Heat treatment of clotting factor concentrates 4. Screening of donors on the basis of history Mother-to-Infant Transmission This vertical transmission is the major cause of pediatric AIDS Three routes are involved: 1. In utero, by transplacental spread 2. Intrapartum, during delivery 3. Via ingestion of HIV-contaminated milk The first two account for most cases.

 HIV infection cannot be transmitted by casual personal contact in the home, workplace, or school, & no convincing evidence for spread by insect bites has been obtained Etiology Aids is caused by HIV, a human retrovirus Pathogenesis Two major targets of HIV infection 1. Immune system 2. Central nervous system Natural History of HIV Infection Three phases reflecting the dynamics of virus-host interaction 1. An early, acute phase 2. A middle, chronic phase 3. A final, crisis phase

Acute phase A self-limited illness that develops in 50% to 70% of adults 3 to 6 weeks after infection Characterized by nonspecific symptoms like sore throat, myalgia, fever, rash, & sometimes aseptic meningitis Characterized too by high levels of virus production, viremea, & widespread seeding of the peripheral lymphoid tissues Chronic phase Represents a stage of relative containment of the virus Immune system is intact at this point, but there is continued HIV replication lasting for several years Patients either are asymptomatic or develop persistent lymphadenopathy & many patients have many opportunistic infections such as thrush (Candida) or herpes zoster

herpes zoster Candida

Crisis phase Characterized by a catastrophic breakdown of host defenses, a marked increase in viremia & clinical disease Patients present a fever of more than 1 months duration, fatigue, weight loss & diarrhea After a variable interval, patients develop serious opportunistic infections, secondary neoplasms &/or neurologic manifestations & the patient is said to have developed fullblown AIDS

AMYLOIDOSIS Characterized by deposition of an abnormal extracellular fibrillar protein, called amyloid in many tissues. Amyloid is derived from many different precursor peptides, deposited as a meshwork of rigid, straight fibrils, 10-15 nm in diameter and with a beta-pleated configuration. Amyloid is recognized by light microscopy in biopsy specimens Amyloid is detected by the Congo Red test giving an orange color. Other stains used are: Sirius red, methyl violet and Iodine.

Classification of Amyloidosis 1. Systemic ( Generalized)- involving several organ systems 2. Localized - when deposits are limited to a single organ, such as the heart Subclassification 1. Primary amyloidosis when associated with some immunocyte dyscrasia 2. Secondary amyloidosis- when it occurs as a complication of an underlying chronic inflammatory or tissue destructive process Symptoms Weakness, fatigue & weight loss- most common initial symptoms Renal disease, hepatomegaly, splenomegaly or cardiac abnormalities

AMYLOIDOSIS

You can't fly a kite unless you go against the wind and have a weight to keep it from turning somersaults. The same with man. No man will succeed unless he is ready to face and overcome difficulties and is prepared to assume responsibilities
-- William J. H. Boetcker