Marta R. GerasymchukM.D., Ph.D., Associate ProfessorPATHOPHYSIOLOGY DEPARTMENT, IFNMU

ALLERGY. ETIOLOGY, PATHOGENESIS, CLINICAL MANIFESTATIONS. AUTOIMMUNE DISEASE

ACTUALITY T he immune system is a finely tuned network that protects the

host against foreign antigens, particularly infectious agents. Sometimes this network breaks down, causing the immune system to react inappropriately.

Inappropriate immune responses may be 1) exaggerated against environmental antigens (allergy); 2) misdirected against the host’s own cells (autoimmunity); 3) directed against beneficial foreign tissues, such as transfusions

or transplants (alloimmunity); or 4) insufficient to protect the host (immune deficiency). All of these can be serious or life threatening.

Exaggerated immune responses (allergy) are the most common, but usually the least life threatening.

CONTENT• Immunity, types, role• Immune response• Immunological tolerance• Autoimmune disorders• Immune deficiency • Allergy, types.

Terminology• Immunity describes the ability of an organism to resist

foreign organisms or invaders which enter its body. • The immune system is designed to protect against

microscopic organisms (bacteria, viruses) and foreign substances which enter an organism from outside its body. The immune system also protects from many cancer cells which arise within our bodies.

• An antigen is any foreign substance which invades the body of an organism, while a pathogen is a living antigen (such as viruses or bacteria) which invade an organism.

FEATURES OF INNATE AND ADAPTIVE IMMUNITYFEATURE INNATE (Natural) ADAPTIVE

Time of response Immediate (minutes/hours) Dependent upon exposure (first: delayed, second: immediate d/t production antibodies)

Diversity Limited to classes or groups of microbes

Very large; specific for each unique antigen

Microbe recognition General patterns on microbes; nonspecific

Specific to individual microbes and antigens (antigen/antibody complexes)

Nonself recognition Yes Yes

Response to repeated infection Similar with each exposure

Immunologic memory; more rapid and efficient with subsequent exposure

DefenseEpithelium (skin, mucous membranes), phagocytes, inflammation, fever

Cell killing; tagging of antigen by antibody for removal

Cellular components Phagocytes (monocytes/ /macrophages, neutrophils), NK cells, DCs

T and B lymphocytes, macrophages, DCs, NK cells

Molecular components

Cytokines, complement proteins, acute-phase proteins, soluble mediators

Antibodies, cytokines, complement system

OVERVIEW OF HUMAN DEFENSESINNATE IMMUNITY

CHARACTE-RISTICS BARRIERS INFLAMMATORY RESPONSE ADAPTIVE (ACQUIRED) IMMUNITY

Level of defense

First line of defense against infection and tissue injury

Second line of defense; occurs as a response to tissue injury or infection

Third line of defense; initiated when innate immune system signals the cells of adaptive immunity

Timing of defense

Constant Immediate response

Delay between primary exposure to antigen and maximum response; immediate against secondary exposure to antigen

Specificity Broadly specific Broadly specific Response is very specific toward “antigen”

Cells Epithelial cells

Mast cells, granulocytes (neutrophils, eosinophils, basophils), monocytes/ macrophages, natural killer (NK) cells, platelets, endothelial cells

T lymphocytes, B lymphocytes, macrophages, dendritic cells

Memory No memory involved No memory involved Specific immunologic memory by T and B lymphocytes

Peptides Defensins, cathelicidins, collectins, lactoferrin, bacterial toxins Complement, clotting factors, kinins Antibodies, complement

Protection

Protection includes anatomic barriers (i.e., skin and mucous membranes), cells and secretory molecules or cytokines (e.g., lysozymes, low pH of stomach and urine), and ciliary activity

Protection includes vascular responses, cellular components (e.g., mast cells, neutrophils, macrophages), secretory molecules or cytokines, and activation of plasma protein systems

Protection includes activated T and B lymphocytes, cytokines, and antibodies

Immunity or body defense mechanism is divided into 2 types, each with humoral and cellular components:

PRIMARY REACTION:

Ag+Ab

SECONDARY REACTION:

TISSUE DAMAGE (in vivo)

AgglutinationPrecipitation

ImmobilisationNeutralisation

LysisComplement

fixation

Ag-Ab complex

a) Primary lymphoid organs:1) Thymus; 2) Bone marrowb) Secondary lymphoid organs:1) Lymph nodes; 2) Spleen;3) MALT (Mucosa-Associated Lymphoid Tissue located in the respiratory tract and GIT).

ORGANS OF IMMUNE SYSTEM

Lymphocytes Monocytes

& macrophages

(1st immune cells to encounter pathogen are macrophages & dendritic cells

Mast cells & basophils

Neutrophils Eosinophils

CELLS OF IMMUNE SYSTEM

Kill virus-infected and neoplastic cellsRelease IFN-γ

CELLS OF THE IMMUNE SYSTEM AND THEIR FUNCTIONSLymphocytes (20-50%) Master of immune system

B-cells (10-15%) Antibody-based humoral reactions, transform to plasma cells, CD19, 20, 21, 23Plasma cells Secrete immunoglobulins

T-cells (75-80%) Cell-mediated immune reactionsa) T-helper cells (CD4+) (60%) Promote and enhance immune reaction by elaboration of cytokinesb) T-suppressor cells (CD8+) (30%) Suppress immune reactions but are directly cytotoxic to antigenc) NK-cells (10-15%) (CD 2, 16, 56) Part of natural or innate immunity; cause antibody- dependent cell- mediated cytotoxicity (ADCC)

Monocytes- Antigen recognition macrophages Phagocytosis (~5%) Secretory function Antigen presentation

Mast cells and Allergic reactions, Wound healing. Once basophils basophils (0-1%) migrate to connective tissue don’t reenter the circulation (called Mast Cell) Neutrophils (40-75%) First line of dense against microorganisms and other small antigens, circulating half-life is 4-10 h Eosinophils (1-6%) Allergic reactions, Helminthiasis; circulate in the blood ~ 30 min, half-life ~ 12 days in the tissue

INNATE AND ADAPTIVE IMMUNITYToll-like receptors in innate immunity

In response to recognition of microbes, phagocytes, DCs, and many other cell types secrete proteins called cytokines, which promote inflammation and microbial killing and enhance protective immune responses. Cells use several receptors to sense microbes; foremost among these are the Toll-like receptors (TLRs), so named because of homology with the Drosophila Toll protein, that recognize bacterial and viral components

a. TLRs are membrane proteins located on the above effector cells.

b. TLRs recognize non-self antigens (molecules) commonly shared by pathogens.

1) Called pathogen-associated molecular patterns(PAMPs)

2) Examples of PAMPs a) Endotoxin in gram-negative bacteria (LPS) b) Peptidoglycan in gram-positive bacteria

c. PAMPs are not present on normal host effector cells. d. Interaction of TLRs on effector cells with PAMPs 1) Initiates intracellular transmission of activating signals to nuclear factor (NF)κβ - the "master switch" to the nucleus. 2) Genes are encoded for mediator production. 3) Mediators are released into the serum or spinal fluid. 4) Innate immunity mediators:

Adhesion molecules for neutrophils (e.g.,

selectins)

Cytokines (tumor necrosis factor, IL 1)

ChemokinesNitric oxide

Reactive oxygen

species (e.g.. peroxide)

Antimicrobial peptides

ANTIGENS

An antigen is any molecule that can stimulate a specific immune response against itself or the cell that carries it. Billions of B and T

lymphocytes are produced during fetal development with the potential to bind to at least 100 million distinct antigens.

Antigens that can bind to a T or B lymphocyte include those present on the cell wall of bacteria or mycoplasmas, the coat of a virus, or on certain pollens, dusts, or foods.

Every cell of a person has surface proteins that would be recognized as foreign antigens by B or T lymphocytes from another person.

If an antigen causes either the B or T lymphocyte to become activated and to multiply or differentiate further, it is an immunogenic antigen.

SELF-ANTIGENSEach individual possesses cell surface antigens that are unique to that individual. These antigens, the MHC proteins, serve as a sort of cellular fingerprint. (In humans, these proteins are sometimes called histocompatibility antigens.) There are two groups of MHC proteins: MHC I and MHC II. The MHC I proteins are found on nearly all cells of the body except the red blood cells. The MHC II proteins are found only on the surface of macrophages and B cells. MHC proteins have two functions: (1) they present self-antigens to T cells, and (2) they bind foreign antigens and present these to T cells. The MHC I molecules bind and present antigens only to cytotoxic T cells. The MHC II molecules bind and present antigens only to helper T cells (both Th1 and Th2 types).

HLA SYSTEM AND MAJOR HISTOCOMPATIBILITY COMPLEX1. Known collectively as the human leukocyte antigen (HLA) system2. Located on short arm of chromosome 63. Gene products are coded for on different loci.4. Gene products are membrane-associated glycoproteins. • Located on all nucleated cells with the exception of mature RBCs 5. HLA genes and their subtypes are transmitted to children from their parents.

HLA association with disease1. HLA-B27 with ankylosing spondylitis2. HLA-DR2 with multiple sclerosis3. HLA-DR3 and -DR4 with type 1 diabetes mellitus

Class I antigens Coded by HLA-A, -B and -C genes Recognized by CD8 T cells & NK cells• Altered class 1 antigens (e.g., virus-infected cell) lead to destruction of the cell.

Class II antigens Coded by HLA-DP, -DQ, and -DR genes Present on antigen-presenting cells, APCs • B cells, macrophages, dendritic cells Recognized by CD4 T cells

Applications of HLA testing1. Transplantation workup• Close matches of HLA-A, -B, & -D loci in both the donor and graft recipient increase the chance of graft survival.2. Determining disease risk Example: HLA-B27-positive individuals have an Increased risk of ankylosing spondylitis.

IMMUNE RESPONSEVirus Bacteria

Th1 Effects Reinforces early, local responsesPromotes inflammatory responses and cell-mediated cytotoxicityMediates type IV (delayed-type) hypersensitivity

Th2 Effects Activates later, systemic responses Promotes humoral and allergic responses Limits inflammatory responses

HUMORAL IMMUNE RESPONSE

IMMUNOGLOBULINS/ANTIBODIESIgG is the most common immunoglobulin and represents approximately 80% of all circulating antibodies. IgG is the main antibody that crosses the placenta from the mother to the fetus during pregnancy. Levels of IgG increase slowly during the primary (first) exposure to an antigen, but increase immediately and to a much greater extent with a second exposure.

IgM antibody is produced first and in highest concentration during the primary exposure to an antigen. IgM is the largest antibody in size.

IgA antibody is most concentrated in secretions such as saliva, vaginal mucus, breast milk, gastrointestinal (GI) and lung secretions, and semen. IgA acts locally rather than through the systemic circulation. Maternal IgA passes to an infant during breastfeeding (as do IgG and IgM to a lesser extent).

IgE is responsible for allergic reactions. It is also the antibody most stimulated during a parasitic infection. TH2 helper cells secrete cytokines that stimulate the production of IgE and activate eosinophils, and thus the response to helminths is orchestrated by TH2 cells.

IgD exists in low concentration in the plasma. Its role in the immune response is not completely clear, although it appears to be important for the maturation and differentiation of all B cells.

Immunoglobul in monomer structureHuman immunoglobulin contains four polypeptides: two identical light chains and two identical heavy chains linked by disulfide bonds to form a monomeric unit. Heavy and light chains are aligned such that the amino portion (NH terminus) of a single heavy and a single light chain form an epitope-binding site (more about this later in the chapter). Each heavy and light chain may be subdivided into homologous regions termed domains.

Light chains, termed K (kappa) or Λ (lambda), are encoded on chromosomes 2 and 22, respectively. There are fivetypes of heavy chains, all encoded on chromosome 14, termed mu (μ), delta (δ), gamma (γ), ep-silon (ε), and alpha (α). The genetically different forms of light chains (K and X) and of heavy chains (μ, δ, γ, ε, and α) are known as iso-types.Immunoglobulin class or subclass is determined by the heavy chain isotype.

is unresponsiveness to an antigen that is induced by exposure of specific lymphocytes to that antigen. Self tolerance refers to a lack of immune responsiveness to one’s own tissue antigens. Central tolerance. The principal mechanism of central tolerance is the antigen-induced deletion (death) of self-reactive T and B lymphocytes during their maturation in central (generative) lymphoid organs (i.e., in the thymus for T cells and in the bone marrow for B cells). In the thymus, many autologous (self) protein antigens are processed and presented by thymic APCs in association with self MHC. Any immature T cell that encounters such a self antigen undergoes apoptosis (a process called deletion, or negative selection), and the T cells that complete their maturation are thereby depleted of self-reactive cells.

Many autologous protein antigens, including antigens thought to be restricted to peripheral tissues, are processed and presented by thymic antigen-presenting cells in association with self-MHC molecules. A protein called AIRE (autoimmune regulator) is thought to stimulate expression of many "peripheral" self-antigens in the thymus and is thus critical for deletion of immature self-reactive T cells. Mutations in the AIRE gene (either spontaneous in humans or created in knockout mice) are the cause of an autoimmune polyendocrinopathy. As with T cells, clonal deletion is also operative in B cells. When developing B cells encounter a membrane-bound antigen within the bone marrow, they undergo apoptosis.

Immunologic Tolerance

Immunologic Tolerance

Peripheral tolerance. Self-reactive T cells that escape negative selection in the thymus can potentially wreak havoc unless they are deleted or effectively muzzled.Several mechanisms in the peripheral tissues that silence such potentially autoreactive T cells have been identified.

The barrier systems preserve an organism against the pathological factors of the external environment. There are external and internal barriers.

• The external barriers are skin, mucous membranes, liver, spleen, lymphatic nodes and other organs, which have the cells of the system of mononuclear phagocytes.

• There are internal barriers in the organism, which are named histohematic barriers. Wall of a capillary has the function of a barrier. The wall of a capillary lets in only the nutritious substances and does not let in the toxins, medicines.

• Examples of internal barriers: 1. hematoencephalic (blood-brain), 2. hematoophtalmic (blood-eye tissue), 3. hematolabirintic (blood-lymph of a labyrinth), 4. hematoovarial (blood-ovarium tissue), 5. hematotestical (blood-testicular tissue)6. hematothyriod (blood-thyriod tissue), 7. placenta (mother’s blood-foetus blood).

• Connective tissue, which surrounds the vessels and penetrates into a tissue, executes the protective function too.

BARRIER SYSTEMS

SYSTEMIC LUPUS ERYTHEMATOSUS• Systemic autoimmune disease. Connective tissue disease that mainly affects the blood, joints, skin, and kidneys1. Antibodies against the host damage multiple tissues via type II (cytotoxic) andtype III (antigen-antibody complex) hypersensitivity.2. More common in women of childbearing age, especially African American females (1 in 245). Female-to-male ratio of 9:1.Etiology and Pathogenesis Genetic1) There is an increased risk for developing SLE in family members.2) Genetic links appear to be located on chromosome 6. Environmental factors are important in exacerbating SLE or triggering its initial onset.Examples : Infectious agents (viruses, bacteria); Ultraviolet light; Estrogen Medications; Extreme stress Drug-induced lupus erythematosus Associated drug: Procainamide, Hydralazine and Isoniazid; Features that distinguish drug-induced lupus from SLE:1) Antihistone antibodies2) Low incidence of renal and CNS involvement3) Disappearance of symptoms when the drug is discontinued

Clinical findingsHematologic

• Autoimmune hemolytic anemia, thrombocytopenia, leukopenia (due to autoAb against cell surface proteins)

Lymphatic1) Generalized painful lymphadenopathy2) Splenomegaly

Musculoskeletal• Small-joint inflammation (e.g., hands) with absence of joint deformity

Skin1) Immunocomplex deposition along basement membrane• Produces liquefactive degeneration2) Malar butterfly rash

Renal• Diffuse prolifera-tive glomeruloneph-ritis (most common glomerulonephritis)

Cardiovascular1) Fibrinous pericarditis with or without effusion2) Libman-Sacks endocarditis (sterile vegetations, small deposits on both sides of the mitral valve; 18% of cases)

Respiratory1) Interstitial fibrosis of lungs2) Pleural effusion with friction rub

Pregnancy-related1) Complete heart block in newborns• Caused by IgG anti-SS-A (Ro) antibodies crossing the placenta2) Recurrent spontaneous abortions• Caused by antiphospholipid antibodies

Fever and weight loss

Renal failure & infection – common causes of death

CRITERION DEFINITION 1. Malar rash Fixed erythema, flat or raised, over the malar eminences, tending to spare the nasolabial folds

2. Discoid rash Erythematous raised patches with adherent keratotic scaling and follicular plugging; atrophic scarring may occur in older lesions

3. Photosensitivity Rash occurring as an unusual reaction to sunlight, reported in patient history or as physician observation 4. Oral ulcers Oral or nasopharyngeal ulceration, usually painless, observed by a physician

5. Arthritis Nonerosive arthritis involving two or more peripheral joints, characterized by tenderness, swelling, or effusion

6. Serositis Pleuritis—convincing history of pleuritic pain or rub heard by a physician or evidence of pleural effusion or Pericarditis—documented by electrocardiogram or rub or evidence of pericardial effusion

7. Renal disorder Persistent proteinuria >0.5 g/dL or >3+ if quantitation not performed or Cellular casts—may be red blood cell, hemoglobin, granular, tubular, or mixed

8. Neurologic disorder

Seizures—in the absence of offending drugs or known metabolic derangements, (e.g., uremia, ketoacidosis, or electrolyte imbalance) orPsychosis—in the absence of offending drugs or known metabolic derangements, (e.g., uremia, ketoacidosis, or electrolyte imbalance)

9. Hematologic disorder

Hemolytic anemia—with reticulocytosis orLeukopenia— <4.0 × 109/L (4000/mm3) total on two or more occasions orLymphopenia— <1.5 × 109/L (1500/mm3) on two or more occasions orThrombocytopenia— <100 × 109/L (100 × 103/mm3) in the absence of offending drugs

10. Immunologic disorder

Anti-DNA antibody to native DNA in abnormal titer orAnti-Sm—presence of antibody to Sm nuclear antigen orPositive finding of antiphospholipid antibodies based on:1) an abnormal serum level of IgG or IgM anticardiolipin antibodies, 2) a positive test for lupus anticoagulant using a standard test, or 3) a falsepositive serologic test for syphilis known to be positive for at least 6 months and confirmed by negativeTreponema pallidum immobilization or fluorescent treponemal antibody absorption test

11. Antinuclear antibody

An abnormal titer of antinuclear antibody (ANA) by immunofluorescence or an equivalent assay at any point in time and in the absence of drugs known to be associated with drug-induced lupus syndrome

Criteria for Classification of Systemic Lupus Erythematosus

Laboratory- testing for SLEa. Serum antinuclear antibody (ANA)(1) Serum ANA is the best screening test for SLE (sensitivity 99%).• False negative test results (have SLE but test is negative) are uncommon.(2) Specificity of serum ANA is only 80%.• False positive results due to other autoimmune diseases (e.g., systemic sclerosis)b. Anti-dsDNA antibodies and anti-Sm (Smith) antibodies(1) Tests used to confirm the diagnosis of SLE• They have high specificity for diagnosing SLE (i.e.. few false positive results)(2) Specificity for anti-dsDNA is 99% and 100% for anti-Sm.c. Anti-Ro antibodies are positive in 25% to 50% of eases.d. Antiphospholipid antibody syndrome is associated with SLE (30% of cases).1. Characterized by autoantibody against proteins bound to phospholipids.2. Anlicardiolipin and lupus anticoagulant are the most common antibodies,i. Lead to false-positive syphilis test and falsely-elevated PTT lab studies,respectively3. Results in arterial and venous thrombosis including deep venous thrombosis,hepatic vein thrombosis, placental thrombosis (recurrent pregnancy loss), & stroke4. Requires lifelong anticoagulationPrognosisa. Improved survival due to advances in diagnosis and treatment• Over 90% now survive for 10 years or moreb. Most common cause of death is infection due to immunosuppression.

SJOGREN SYNDROMEAutoimmune destruction of lacrimal and salivary glands

Lymphocyte-mediated damage (type IV hypersensitivity) with fibrosis

Classically presents as dry eyes (keratoconjunctivitis), dry mouth (xerostomia), and recurrent dental carries in an older woman (50-60 years)—"Can't chew a cracker, dirt in my eyes"

Characterized by ANA and anti-ribonucleoprotein antibodies (anti-SS-A/Ro & anti-SS-B/La)

Often associated with other autoimmune diseases, especially rheumatoid arthritis

Increased risk for B-cell (marginal zone) lymphoma, which presents as unilateral enlargement of the parotid gland late in disease course

Salivary glands are often enlarged as a result of lympho-cytic infiltrates. Extraglandular manifestations include synovitis, pulmonary fibrosis, and peripheral neuropathy.

• Excessive production of collagen that primarily targets the skin (scleroderma), GI tract, lungs, and kidneys1. Occurs predominantly in women of childbearing age2. Pathogenesisa. Small-vessel endothelial cell damage produces blood vessel fibrosis and ischemic injury.b. T-cell release of cytokines results in excessive collagen synthesis.c. Stimulatory autoantibodies against platelet-derived growth factor

SYSTEMIC SCLEROSIS (SCLERODERMA)

Laboratory findings in systemic sclerosis:a. Serum ANA is positive in 70% to 90% of cases.b. Anti-topoisomerase antibody is positive in 30% of cases.• Extractable nuclear antibody to Scl 70.

Respiratory1) Interstitial fibrosis2) Respiratory failure (most common cause of death)

CREST syndrome• Limited sclerosis1) C—calcification, anti-centromere antibody2) R—Raynaud's phenomenon 3) E—Esophageal dysmotility4) S—sclerodactyly (i.e., tapered, claw-like fingers)5) T—telangiectasias (i.e., multiple punctate blood vessel dilations)

Renal1) Vasculitis involving arterioles (i.e., hyperplastic arteriolosclerosis) & glomeruli2) Infarctions, malignant hypertension

Gastrointestinal(1) Dysphagia for solids and liquids(a) No peristalsis in the lower two thirds of the esophagus (smooth muscle replaced by collagen)(b) Lower esophageal sphincter relaxation with reflux(2) Small bowel(a) Loss of villi (malabsorption)(b) Wide-mouthed diverticula (bacterial overgrowth)(c) Dysmotility (cramps and diarrhea)

Skin(1) Skin atrophy and tissue swelling beginning in the fingers and extending proximally(2) Parchment-like appearance(3) Extensive dystrophic calcification in subcutaneous tissue(4) Tightened facial features (e.g., radial furrowing around the lips)

Raynaud's phenomenon(1) Sequential color changes (white to blue to red) caused by digital vessel vasculitis & fibrosis• Most common initial complaint (70% of cases)(2) Tapered fingers often with digital infarcts

Clinical findings

Treatment: D-Penicillamine; recombinant

human relaxin

Laboratory findings:

Anticentromere antibodies in 50% to 90% of cases

A. Raynaud phenomenon generally presents as episodic modified blood flow of the digits, usually in response to exposure to cold or stress. The classic triphasic color change progresses from white (ischemia) to blue (deoxygenation) then red (reperfusion). B. Common early symptoms of SSc include swelling, skin tightening and contractures of the fingers with polyarthralgia. C. Gradual thickening of the skin of the face and presence of teleangiectasias is characteristic of advanced SSc. D. Digital ulcers are one of the most frequent clinical manifestations of microangiopathy in patients with SSc. A decreased number of capillary loops is associated with progressive thickening of the skin and the development of ulcers in the late stages of the disease. Abbreviation: SSc, systemic sclerosis.

Systemic Sclerosis: Scleroderma, Hands and FaceThis 55 year-old man with a 16-year history of diffuse systemic sclerosis and positive Scl-70 antibody has characteristic fibrotic, taut skin with atrophy over the bony prominences. Note the calcification in the left hypothenar region, atrophy of hypothenar muscles, digital pitting in pulp of left long finger, and flexion contractures of proximal interphalangeal joints. Terminal digit resorption allows nails to curve over fingertips (upper left). Also note the temporal muscle atrophy, tight shiny skin over forehead and cheeks, variations of pigment (nares, forehead, ear, neck), loss of nasolabial folds, and retraction of lips (right).

IMMUNODEFICIENCYDISORDERS

Defects in B cells. T cells,

complement, or phagocytic cells

Risk factors for immune disorders

1. Prematurity2. Autoimmune diseases (e.g.. systemic lupus erythematosus)3. Lymphoproliferative disorders (e.g., malignant lymphoma)4. Infections (e.g.. human immunodeficiency virus, HIV)5. Immunosuppressive drugs (e.g.. corticosteroids)

B-cell disordersDISEASE DEFECT(S) CLINICAL FEATURES

Bruton's agammaglobulinemia

Failure of pre-B cells to become mature B cellsMutated tyrosine kinaseX-linked recessive disorder

Sinopulmonary infectionsMaternal antibodies protective from birth to age of 6 monthsImmunoglobulins

IgA deficiency Failure of IgA B cells to mature into plasma cells

Sinopulmonary infections; giardiasisAnaphylaxis if exposed to blood products that contain IgA IgA and secretory IgA

Common variable immunodeficiency

Defect in B-cell maturation to plasma cellsAdult immunodeficiency disorder

Sinopulmonary infections (90-100%), Gl infections (e.g., Giardia), pneumonia, autoimmune disease(idiopathic thrombocytopenic purpura, autoimmune hemolytic anemia), malignancy (25%).Common pathogens: Actinomyces israeli, Streptococcus pneumoniae, Haemophilus influenzae; chronic infections – Staphylococcus aureus, Pseudomonas aeruginosa. Immunoglobulins

- Ig G, not detectible Ig A & Ig M.- T cells, normal function.- diagnosed in male infants, 9-12 month.

Clinical manifestations:- Pneumonia, otitis media, meningitis, sinusitis, septicemia (Haemophilus influenzae type b, Streptococcus pneumoniae, Neisseria meningitidis);-The recurrent infections can lead to tissue destruction & injury;- infants can grow normally if treated with antibiotics & recurrent administration of human immune globulin; - passive immunotherapy isn’t always effective. Many children die before the age 6.- If the chield survives to adulthood, life expectancy is decreased &large joint arthritis is common.

Mutations in the gene for Bruton’s tyrosine kinase (Btk) – an enzyme involved in intracellular signaling from several B-cell receptors, including the IgM B-cell antigen receptor, the IL-5 receptor, and the IL-6 receptor. Ineffective signaling results in the arrest of the development in the bone marrow of early cells in the B-cell lineage into mature B cells.

The most commonly diagnosed immune deficiency. Terminal differentiation of mature B cells to plasma cells is blocked. Characterized by hypogammaglobulinemia, but the particular class of

antibody that is varies: most have low amounts of IgG, which may or may not be accompanied by levels of IgA or IgM, or both, with normal numbers of B cells.

Multiple genetic defects in terminal differentiation account for this condition, although the specific defects have not been identified in most people.

The age of onset of symptoms, such as recurrent bacterial respiratory tract infections, is generally later than most primary immune deficiencies (symptoms occurs much later, usually between the ages of 15 and 35 years, and distribution of disease between the sexes is equal).

Secondary complications include: - arthritis (infectious and noninfectious), chronic lung disease

COMMON VARIABLE IMMUNODEFICIENCY

-GIT symptoms (malabsorption, chronic diarrhea, hepatitis), - autoimmune disease (anemia, thrombocytopenia, endocrine diseases), - cancer (of the lymphoid system, skin, and gastrointestinal tract).½ of persons with the disorder have evidence of abnormal T-cell immunity, suggesting that this syndrome is a complex immunodeficiency.

HYPER-lgM SYNDROME

Characterized by elevated IgM Inability of T cells to induce D cell isotype switching (heavy chain) Due to mutated CD40L (on helper T cells), located on X chromosome, or CD40 receptor (on B cells); notably enzyme called activation-induced deaminase.1. Second signal cannot be delivered to helper T cells during B-cell activation.2. Consequently, cytokines necessary for immunoglobulin class switching are not produced, Low IgA, IgG, and IgE result in recurrent pyogenic infections (due to poor opsonization), especially at mucosal sites. Susceptible for intracellular pathogens, Pneumocystis jiroveci

DISEASE DEFECT(S) CLINICAL FEATURES

DiGeorge syndrome

Failure of third and fourth pharyngeal pouches to developThymus and parathyroid glands fail to develop

Hypoparathyroidism (tetany); absent thymic shadow on radiograph; Pneumocystis jiroveci pneumoniaDanger of graft-versus-host reactionFacial abnormalities, cardiac malformations; depression of T-cell number, & absence of T-cell responses

MHC class I deficiency

Failure of TAP 1 molecules to transport peptides to endoplasmic reticulum

CD8+ T cells deficient,CD4+ T cells normal,Recurring viral infections, normal DTH, normal Ab production

Bare Lymphocyte Syndrome/ MHC class II deficiency

Failure of MHC class II expression, defects in transcription factors

T cells present and responsive to nonspecific mitogens, no GVHD, deficient CD4+ T cells, hypogammaglobulinemia. Clinically observed as a severe combined immunodeficiency.

T-Cell Disorder Recurrent infections caused by intracellular pathogens (fungi, viruses, protozoa)

Facial Anomalies Associated with DiGeorge Syndrome

DIGEORGE SYNDROME (congenital Thymic aplasia or hypoplasia)

- Lack of thymus development, - Partial or complete absence of the parathyroid gland (resulting in blood calcium levels), - Major structural defects in the heart and the aorta (resulting in inadequate blood flow and inadequate oxygenation of the tissues), - Abnormal facial characteristics (e.g., underdeveloped chin, low-set ears, shortened structure of the upper lip). The facial disorders can include hypertelorism (i.e., increased distance between the eyes); micrognathia (i.e., fish mouth); low-set, posteriorly angulated ears; split uvula; and high-arched palate. - Urinary tract abnormalities also are common.- The most common presenting sign is hypocalcemia and tetany that develops during the first 24 hours of life. It is caused by the absence of the parathyroid gland and is resistantto standard therapy.

CLINICALLY:

The defect is attributed usually to deletions on chromosome 22, 22q11.2 (some deletions also have been identified on chromosome 10); about 25% of which are inherited. The deleted region encodes information for formation of organs (structures that give rise to the thymus, parathyroid glands, and portions of the face and aortic arch) that originate from the 3rd and 4th pharyngeal pouches during the 12th week of gestation.

DISEASE DEFECT(S) CLINICAL FEATURES

Severe combined immunodefi-ciency (SCID)

Adenosine deaminase deficiency (15%); autosomal recessive disorder; adenine toxic to B and T cells: deoxynucleoide triphosphate precursors for DNA synthesis;Other disorders: stem cell defect

Defective cell-mediated immunity; Immunoglobulins;Treatment: gene therapy, bone marrow transplant (patients with SCID do not reject allografts).

Wiskott-Aldrich syndrome

Progressive deletion of B and T cellsX-linked recessive disorder

Symptom triad: eczema, thrombocytopenia, sinopulmonary infections; Associated risk of malignant lymphoma; Defective cell-mediated immunity. IgM, normal IgG, IgA and IgE.

Ataxia-telangiectasia

Mutation in DNA repair enzymesThymic hypoplasiaAutosomal recessive disorder

Cerebellar ataxia, telangiectasias of eyes and skin; Risk of lymphoma and/or leukemia; adenocarcinoma; Serum α-fetoprotein; IgA 50-80%, IgE, IgM low molecular weight variety, IgG2 or total IgG; T cell function

Defects in common γ chain of IL-2 receptor (present in receptor for IL-4, -7, -9, -15)Adenosine deaminase deficiency (results in toxic metabolic products in cell)

Chronic diarrhea; skin, mouth, & throat lesions; opportunistic (fungal) infections; low levels of circulating lymphocytes; cells unresponsive to mitogens

Rag1 or rag2 gene nonsense mutations Total absence B + T cells

COMBINED B- AND T-CELL DISORDERS

a. Sexual transmission (75% of cases)1) Most common cause is the man-to-man transmission by anal intercourse;2) Heterosexual transmission is the most common cause in developing countries;3) Virus enters blood vessels or dendritic cells in areas of mucosal injury.b. Intravenous drug abuse• Rate of HIV infection is markedly in female sex partners of male intravenous drug abusers.c. Other modes of transmission1) Vertical transmission (mother - baby): Transplacental route, blood contamination

during delivery, breast-feeding Most pediatric cases of AIDS are due to transmission of virus from mother to child.2) Accidental needlestick: Risk per accident is 0.3%. Most common mode of infection in health care workers3) Blood products

Acquired immunodeficiency syndrome

Body fluids containing HIV1) Blood, semen, breast milk2) Virus can not enter intact skin or mucosa. Etiologya. RNA retrovirusb. HIV-1 is the most common cause in the USA, Europe, Central Arica.c. HIV-2 is the most common cause in West Africa and India. Pathogenesisa. HIV envelope protein (gp120) attaches to the CD4 molecule of T cells.b. HIV infects CD4 T cells, causing direct cytotoxicity.c. Infection of non-T cells:1) Can infect monocytes and macrophages in tissue (e.g., lung, brain)2) Can infect dendritic cells in mucosal tissueDendritic cells transfer virus to B-cell germinal follicles,3) Macrophages and dendritic cells are reservoirs for virus. Loss of cell-mediated immunityd. Reverse transcriptase:1) Converts viral RNA into pro-viral 2) double-stranded DNA2) DNA is integrated into the bust DNA.

Acquired immunodeficiency syndrome

Clinical findingsa. Acute phase• Mononucleosis-like syndrome 3 to 6 weeks after infectionb. Latent (chronic) phase1) Asymptomatic period 2 to 10 years after infection2) CD4 T-cell count greater than 500 cells/mm33) Viral replication occurs in dendritic cells (reservoir cells) in germinal follicles of lymph nodes.• Cytotoxic T cells control but do not clear HIV reservoirs.c. Early symptomatic phase1) CD4 T-cell count 200 to 500 cells/mm32) Generalized lymphadenopathy3) Non-AlDS-defining infections, including hairy leukoplakia, or Epstein-Barr virus (EBV)-caused glossitis, oral candidiasis.4) Fever, weight loss, diarrhea.• Most common CNS fungal infection in AIDS: cryptococcosisd. AIDS: Criteria - HIV-positive with CD4 T-cell count of 200 cells/mm3 or less or an AIDS defining conditionMost common AIDS-defining infections: Pneumocystis Jiraveci pneumonia, systemic candidiasisAIDS-defining malignancies: Kaposi's sarcoma, Burkitt's lymphoma (EBV), primary CNSlymphoma (EBV)Causes of death: Disseminated infections (cytomegalovirus, Mycobacterium avium complex)

Acquired immunodeficiency syndromeHIV Rash

HUMAN IMMUNODEFICIENCY VIRUS (HIV) -ASSOCIATED APHTHOUS ULCER. A, This large ulcer extends from the uvula to the soft palate. These lesions are frequent in patients with acquired immunodeficiency syndrome (AIDS) and may occur on the tongue or buccal mucosa or in the hypopharynx. They may become large, simulating an infectious or neoplastic process. B, Deep ulcer on the lateral aspect of the tongue. Note in the distance a well-circumscribed, similarappearing ulcer is present on the hard palate. C, Well-circumscribed, clean-based ulcer on the tongue.

D, Multiple ulcerations on the lower lip. This patient with severe odynophagia also had a large idiopathic esophageal ulceration.

Acquired immunodeficiency syndromeImmunologic abnormalities1) Lymphopenia (low CD4 T-cell count)2) Cutaneous anergy (defect in cell-mediated immunity)3) Hypergammaglobulinemia (due to polyclonal B-cell stimulation by EBV)4) CD4:CD8 ratio < 1 CD4 count and risk for certain diseases1) 700 to 1500: normal2) 200 to 500; oral thrush, herpes zoster (shingles), hairy leukoplakia3) 100 to 200: Pneumocystis pneumonia, dementia4) Below 100: toxoplasmosis, cryptococcosis, cryptosporidiosis5) Below 50: CMV retinitis. Mycobacterium avium complex, progressive multifocalleukoencephalopathy, primary central nervous system lymphomaPregnant women with AIDS• Treatment with a reverse transcriptase inhibitor reduces transmission to newborns toless than 8%.

Allergy (from Greek “allos” – “other”, “ergon” – “action”) is the state of the increasing sensitiveness of the organism to the repeated penetrating of allergen which is characterized by immunological mechanisms

and self injury.

Allergy is an immune response, which is followed by damage of own tissues.

Allergic diseases – is a group of diseases, in development base of which damage lies, caused by an immune reaction on allergens.

Allergic diseases are widely spread among people. It is considered that they cover about 10 % of earth population. In different countries

these sizes vacillate from 1 to 50 % and more.

General etiology of allergic diseases

The cause of allergic diseases is the allergen, the conditions of their appearing are the specific peculiarities of the environment and state of organism reactivity.

Allergen – is a substance that causes development of an allergic reaction.

Allergens have all properties of antigens (macromolecularity, mainly protein nature, foreign for a particular organism). However allergic reactions can be caused by substances of not only antigen nature, but also substances, not possessing these properties. To this group belong many officinal preparations, bacterial products, polysaccharides, simple chemical substances (bromine, iodine, chrome, nickel). These substances are called

haptens. While entering the organism they become antigens (allergens) only after binding with tissues proteins. Here with complex antigens, which sensitize the organism are formed.

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The classification by P.Gell, R.Coombs is

widely spread in the world. It is based on pathogenic principle.

By Rought (in 1980) V type - stimulating.

I – IgE, II, III – IgM, G,

IV – T-effectors, V - IgM, G

Soluble mediators, performed actors-fast reactions of less than 30 min

Soluble mediators, performed actors-slower reactions of less than 8 hours

Soluble mediators, performed actors-slower reactions of less than 8 hours

Cellular mediators, performed actors-slow reactions of more than 1 day

THE PATHOGENESIS OF ALLERGIC REACTIONS

STAGE I: IMMUNOLOGICAL

STAGE II: PATHOCHEMICAL CHANGES

STAGE III: PATHOPHYSIOLOGICAL CHANGES

In the development of allergic reaction there are

three stages:

• 1. Immunological stage. It covers all the changes in immune system during the penetration of an allergen into the organism, formation of

antibodies or sensitized lymphocytes and their binding with the repeatedly entering allergen.

• 2. Pathochemical stage. Its sense is in formation of biological active substances. The stimulus to their formation is the binding of allergen to antibodies or sensitized lymphocytes at the end of immunological stage.

• 3. Pathophysiological stage. It is described by pathogenic action of formed mediators onto cells, organs and tissues of the organism with a clinical display.

• Sensibilization is the immunologically mediated increasing sensitiveness of the organism to the allergens. • Sensibilization (sensitizing) are:

– active (independent production of immunoglobulin by the organism)– passive (introduction of the ready antibodies from

actively sensitized animals). The synthesis of the antibodies begins on the 3rd - 4th day after the first penetrating of the allergen and achieves the maximum in 2 weeks.

TYPE I HYPERSENSITIVITY REACTION

• IgE and IgG4 are formed as an answer to penetrating of allergen into the organism. They get fixed on the mast cells and basophiles of blood.

• These cells have on their surface Fc-receptors for immunoglobulin. The

state of sensitization of the organism appears. If the same allergen again gets into the organism or it still stays in the organism after the first penetration, connection of antigen with IgE-antibodies occurs.

The same thing is observed with IgG4. They bind with their receptors on basophiles, macrophages, eosinophiles, trombocytes.

Depending on the quantity of molecules of IgE-antibodies connected to antigen, quantity of antigen we can observe either inhibition of activity of the cell or its activation and transfer of the process to the next, pathochemical stage.

1. Initial antigen contact

Stage II (pathochemical)

• At the repeated penetrating the allergen associates with the Fc-fragment of IgE activating of basophiles activation of arachidonic acid cascade is liberation of prostaglandins and leukotrienes degranulation of mast cells

(the freeing of biologically active substances (BAS).

Stimulation of H1 promotes to contraction of smooth muscles, endothelial cells and postcapillary part of

microcirculation. This leads to increasing of permeability of vessels, development of edema and inflammation.

Stimulation of H2 causes the opposite effects. Besides this releasing of histamine from basophile leucocytes and

from the lungs is diminished through them, the function of the lymphocytes modulates, formation of migration ingibitory factor

(MIF) by T-lymphocytes gets oppressed, releasing of lysosome enzymes by neutrophile leucocytes diminishes as well. In many cases the increasing of quantity of histamine in blood is observed in the intensive stage of bronchial asthma, nettle-rash, officinal allergy.

• Stage III. • Under the influence of mediators the permeability of vessels and chemotaxis of

neutrophiles and eosinophiles increase, which leads to development of inflammatory reaction.

• The increasing of permeability of vessels promotes the exit of fluid, immunoglobulins and complement into tissues. With the help of mediators and also through the IgE-antibodies, the cytotoxic effect of macrophages is activated, secretion of enzymes, prostaglandins and leukotriens, trombocyte activating factor is stimulated.

• The released mediators cause also a damaging action onto cells and connective tissue structures.

• Bronchospasm develops in respiratory organs. These effects are clinically manifested by attacks of bronchial asthma, rhinitis, conjunctivitis, nettle-rash, skin itch, diarrhea.

• They distinguish the local reactions of the anaphylactic type. E.g.: bronchial asthma, pollinosis (or pollen disease, grass pollen allergy, hay fever), nettle-rash (or hives) and general ones (anaphylactic shock).

IgE antibody-mediated activation of mast cells (effector cells) produces an inflammatory reaction.1. IgE antibody production (sensitization) a. Allergens (e.g., pollen, drugs) are first processed by APCs (macrophages or dendritic cells). b. APCs interact with CD4 Th2 cells, causing interleukins (ILs) to stimulate B-cell maturation. c. IL-4 causes plasma cells to switch from IgM to IgE synthesis. d. IL-5 stimulates the production and activation of eosinophils.2. Mast cell activation (re-exposure) a. Allergen-specific IgE antibodies are bound to mast cells. b. Allergens cross-link IgE antibodies specific for the allergen on mast cell membranes. c. lgE triggering causes mast cell release of preformed mediators.1) Early phase reaction with release of histamine, chemotactic factors for eosinophils, proteases2) Produces tissue swelling and bronchoconstriction d. Late phase reaction1) Mast cells synthesize and release prostaglandins and leukotrienes,2) Enhances and prolongs acute inflammatory reaction3. Tests used to evaluate type I hypersensitivity a. Scratch test (best overall sensitivity)• Positive response is a histamine-mediated wheal-and-flare reaction after introduction of an allergen into the

skin. b. Radioimmunosorbent test• Detects specific IgE antibodies in serum that are against specific allergens.4. Clinical examples: Atopic disorders: hay fever, eczema, hives, asthma, reaction to bee sting Drug hypersensitivity: penicillin rash or anaphylaxis.

TYPE I (IMMEDIATE) HYPERSENSITIVITYSummary

Anaphylactic shock

Anaphylactic shock develops in severe complication. Spasm of smooth muscles of internal organs with clinical manifestation of bronchospasm (cough, expiratory breathlessness),

spasm of gastro-intestinal tract muscles (spastic pain in the whole abdomen, nausea, vomiting, diarrhea),

spasm of uterus in women (pain below abdomen) are observed.

Spastic phenomena are worsened by edemas of mucous covers of internal organs, during the edema of larynx the picture of asphyxia may develop.

The arterial pressure is sharply decreased, the heart insufficiency, ischemia of brain, seizes paralysis develop, danger for the life of the patient appears.

CYTOTOXIC REACTION

• Antigens: a) components of membranes of own cells (unchanged and changed under the action of

different factors); b) antigens are fixed (adsorbed) on cellular membranes (for example, medicinal preparations); c) non-cellular components of tissues (collagen, myelin).• Antibodies: IgG1, IgG2, IgG3, rare Ig M and Ig A. • Mechanisms of tissue injury: opsonization and phagocytosis of cells;

complement- and Fc receptor-mediated recruitment and activation of neutrophils and macrophages; abnormalities in cellular functions (hormone/receptor signaling)

THE PATHOGENESIS OF THE CYTOTOXIC TYPE ALLERGIC REACTIONS► Stage II:Mediators of the cytotoxic type allergic reactions:► Complement components; Lysosomal enzymes;► Oxygen’s radicals; TNF;► Perforin (channel-forming protein).The damage of the cell with the antigen properties may be caused by three reasons: ► the 1st variant – complement-mediated cytotoxicity. ► the 2nd variant – antibody-mediated immune clearance (phagocytosis). ► the 3rd variant – antibody-dependent [cell-mediated] cytotoxicityStage III:► Remedies [medicamentous] allergy;► Hemolytic anemia (illness) of newborns;► Post transfusion reactions (shock) in incompatible blood transfusion after the groups of АВО or Rhesus factor;► Auto allergic diseases.

Cytotoxic type of the allergy can be a manifestation of officinal allergy with the development of leucocytopenia, trombocytopenia, hemolytic anemia etc. This may also happen in blood transfusion and also in rhesus incompatibility of mother and fetus.

Type II (cytotoxic) hypersensitivity

Antibody-dependent cytotoxic reactions1. Complement-dependent reactionsa. Lysis (IgM-mediated)1) Antibody (IgM) directed against antigen on the cell membrane activates the complement system, leading to lysis of the cell by the membrane attack complex.2) Example: IgM types of cold immune hemolytic anemias; Transfusion of group A blood (contains anti-B-lgM antibodies) into a group B individualb. Lysis (IgG-mediated)1) IgG attaches to basement membrane/matrix → activates complement system → C5a is produced (chemotactic factor) → recruitment of neutrophils/monocytes to the activation site → release of enzymes, reactive oxygen species → damage to tissue2) Example: Coodpasture’s syndrome with lgG antibodies directed against pulmonary and glomerular capillary basement membranes; Acute rheumatic fever with IgG antibodies directed against antigens in heart, skin, brain, subcutaneous tissue, joints.c. Phagocytosis1) Fixed macrophages (e.g., in spleen) phagocytose hematopoietic cells (e.g., RBCs)coated by IgG antibodies or complement (C3b).2) Example: Warm (IgG) immune hemolytic anemia; ABO hemolytic disease of the newborn. • Croup O mother has anti-A,B-IgG antibodies that cross the placenta and attach to fetal blood group A or B red blood cells.

DISEASE TARGET ANTIGEN MECHANISM OF PATHOGENESIS

CLENICAL MANIFESTATTIONS

CytotoxicAutoimmune hemolytic anemia (HDNB)

RBC membrane proteins (Rh, I Ags)

Opsonization, phagocytosis, & complement-mediated destruction of RBCs

Hemolysis, anemia

Acute rheumatic fever

Streptococcal cell-wall Ag-Ab cross-reacts with myocardial Ag

Inflammation, macrophage activation

Myocarditis, artritis

Goodpasture syndrome

Type IV collagen in basement membranes of kidney glomeruli & lung alveoli

Complement- & Fc-receptor-mediated inflammation

Nephritis, lung hemorrhage, linear Ab deposits

Transfusion reaction

ABO blood glycoproteins Ig M isohemagglutinins formed naturally in response to normal bacterial flora cause opsonization + complement activation

Hemolysis

Autoimmune thrombocytopenic purpura

Platelet membrane proteins Ab-mediated platelet destruction through opsonization &complement activation

Bleeding

TYPE II HYPERSENSITIVITIES

Type II (cytotoxic) hypersensitivity2. Complement-independent reactions:a. Antibody IgG-dependent cell-mediated cytotoxicity Cells are coated by IgG → leukocytes (neutrophils, monocyte, NK cells) bind to IgG → activated cells release inflammatory mediators causing Iysis of the cells. Example: killing virus-infected cells or tumor cells.b. Antibody IgE-dependent cell-mediated cytotoxicity• Helminth in tissue is coated by IgE antibodies → eosinophil IgE receptors attachto the IgE → eosinophils release major basic protein, which kills the helminth.c. IgG autoantibodies directed against cell surface receptors → impair function of the receptor (e.g.. anti-acetylcholine receptor antibodies in myasthenia gravis) or stimulate function (e.g., anti-thyroid-stimulating hormone receptor antibodies in Craves' disease)Tests used to evaluate type II hypersensitivity:a. Direct Coombs’ test detects IgG and C3b attached to RBCs.b. Indirect Coombs’ test detects antibodies (e.g., anti-D) in serum.

DISEASE TARGET ANTIGEN MECHANISM OF PATHOGENESIS

CLENICAL MANIFESTATTIONS

Non-cytotoxicMyasthenia gravis Acetylcholine receptor Ab inhibits acetylcholine

binding, down-modulates receptors.

Muscle weakness, paralysis

Graves disease TSH receptor Ab-mediated stimulation of TSH receptors

Hyperthyroidism followed by hypothyroidism

Type II (non-insulin-dependent) diabetes

Insulin receptor Ab inhibits binding of insulin

Hyperglycemia

Pernicious anemia Intrinsic factor of gastric parietal cells

Neutralization of intrinsic factor, decreased absorption of vitamin B12

Abnormal erythropoiesis, anemia

TYPE II HYPERSENSITIVITIES

Activation of the complement system by circulating antigen-antibody complexes (e.g.,

DNA - anti-DNA complexes)First exposure to antigen → synthesis of antibodies;Second exposure to antigen:a. Deposition of antigen-antibody complexesb. Complement activation, producing C5a, which attracts neutrophils that damage tissueArthus reactiona. Localized immunocoinplex reactionb. Example: farmer's lung from exposure to thermophilic actinomycetes, or antigens, in airTest used to evaluate type III hypersensitivitya. Immimofluorescent staining of tissue biopsiesb. Example: glomeruli in glomerulonephritis

TYPE III (IMMUNOCOMPLEX) HYPERSENSITIVITY

The inflammation may lead to formation of ulcers, hemorrhages, thrombosis is possible in the vessels. This type of allergic reactions is the prominent one in development of serum, some cases of officinal and food allergy, some autoallergic diseases (rheumatoid arthritis, systemic red lupus erythematosus). In case of massive activation of complement anaphylactic shock, bronchial asthma may develop.

Pathophysiological stage. Usually immune complexes are placed on vessels of cannalicular apparatus of kidneys, inflammation with alteration, exudation and proliferation (glomerulonephritis) develops, in case if the complexes are placed in the lungs alveolitis appears, in skin – dermatitis.

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In systemic lupus erythematosus (a.k.a. SLE, lupus), nuclear components of disintegrating white blood cells elicit IgG production

Immune complexes aggregate in the skin and organs, causing rash and lesions

Rheumatoid arthritis (RA) is an inflammatory condition resulting in accumulation of immune complexes in joints

Disease Antigen Involved Clinical Manifestations

Systemic lupus erythe-matosus

dsDNA, Sm, other nucleoproteins

Nephritis, arthritis, vasculitis, butterfly facial rush

Rheumatoid arthritis

Ig M versus IgG Fc region

Joint pain, erosions

Poststrepto-coccal glome-rulonephritis

Streptococcal cell wall Ags (may be “planted” in glomerular basement membrane

Nephritis, “lumpy-bumpy” deposits

Serum sickness

Various proteins Arthritis, vasculitis, neprhritis

Arthus reaction

Any injected protein Local pain and edema

Examples of type III Hypersensitivities

RA

SLE

Serum sickness

1. Initial contact with antigen

Cell-mediated hypersensitivity reactionImmunological stage. ☻ The foreign antigen is phagocyted by macrophages and get to T-helpers. ☻ At the same time macrophages secrete  IL-1, which stimulates T-helpers. The latest excrete the growth factor pro-T-lymphocytes – IL-2, which activates and supports proliferation of antigen stimulated T-cells. ☻ This process leads to formation of sensitized lymphocytes. ☻ They belong to T-lymphocytes and in the cell membrane they have receptors of the antibody type, which are able to connect with the antigen. ☻ In case of repeated penetration of the allergen into the organism it binds with the sensitized lymphocytes.

Pathochemical stage. This leads to morphological, biochemical and functional change in lymphocytes.

They are presented by blast transformation and proliferation, increasing of synthesis of DNA, RNA and proteins and excretion of different mediators, which are called lymphokines. With the help of lymphokines (MIF, interleukines, chemotaxic factors, factor of transfer) mobilization of different cells (macrophages, polymorph-nuclear), increasing of chemotaxic activity and placing in the site of allergen occur. • MIF promotes accumulation of macrophages in the site of allergic damage, increases their activity and phagocytosis. It takes part in formation of granulems during infectious-allergic diseases, increase the ability of macrophages to destroy certain kinds of bacteria. • There are several kinds of chemotaxic factors, each of which is called chemotaxis of leukocytes – macrophages, neutrophiles, eosinophiles and basophiles. Lymphotoxins cause damage and destroying of all different target-cells. • Interferon is secreted by lymphocytes and under the influence of α-interferon and nonspecific mitogens. It acts a modulating influence on cellular and humoral mechanisms of immune reaction. • Besides lymphokines, lizosome enzymes also provide a damaging activity. They are released during phagocytosis and destroying of cells. Kallikreine-kinine system is also activated. Histamine doesn’t play a big role in this type of allergic reactions.

Pathophysiological stage. A particular form of lymphokines (lymphotoxin, interferon) shows a cytotoxic action and decreases activity of cell. In allergic reaction of delayed type damaging action may develop in several ways:

• 1) direct cytotoxic action of sensitized T-lymphocytes on target-cells, which acquired autoallergen properties;

• 2) cytotoxic activity of T-lymphocytes, mediated by lymphotoxin; • 3) releasing of lysosome enzyme, which damage tissue structures

during phagocytosis.

• Inflammation that is associated to immune reaction by action of mediators is a component of allergic reaction of delayed-type. Nevertheless inflammation is at the same time a factor of damage of function of the organs.

• Allergic reactions of delayed type make the base of development of infectious-allergic diseases (tuberculosis, lepra, brucellosis, syphilis), rejection of transplant, and autoallergic diseases (disturbance of nervous system, endocrine glands etc.).

Mechanisms of T cell-mediated (type IV) hypersensitivity reactions

A, In delayed type hypersensitivity reactions, CD4+ T cells (and sometimes CD8+ cells) respond to tissue antigens by secreting cytokines that stimulate inflammation and activate phagocytes, leading to tissue injury. B, In some diseases, CD8+ cytolytic T lymphocytes (CTLs) directly kill tissue cells. APC, antigenpresenting cell.

Type IV hypersensitivity Antibody-independent T cell-mediated reactions (cellular-mediated immunity, CMI)Functions of CMIa. Control of infections caused by viruses, fungi, helminths, mycobacteria, intracellular bacterial

pathogensb. Graft rejectionc. Tumor surveillanceTypes of reactions:a. Delayed reaction hypersensitivity (DRH)• CD4 cells interact with macrophages (APCs with MHC class II antigens), resulting in cytokine

injury to tissue.b. Cell-mediated cytotoxicity1) CD8 T cells interact with altered MHC class I antigens on neoplastic, virus-infected, or donor

graft cells, causing cell lysis.2) Contact dermatitis → CD8 T cells attack antigens in skin (e.g.. poison ivy, nickel).Test used to evaluate type IV hypersensitivity:a. Patch test to confirm contact dermatitis.• Example: suspected allergen (e.g.. nickel) placed on an adhesive patch is applied to the skin to

see if a skin reaction occurs.b. Skin reaction to Candida.c. Quantitative count of T cells.d. Various mitogenic assays.

Transplantation ImmunologyFactors enhancing graft viability 1. ABO blood group compatibility between recipients and donors2. Absence of preformed anti-HLA cytotoxic antibodies in recipients• People must have previous exposure to blood products to develop anti-HLA cytotoxic antibodies.3. Close matches of HLA-A, -B, and -D loci between recipients and donors4. Chance of a sibling in a family having another sibling with a 0, 1, or 2 haplotype match.Types of grafts1. Autograft (i.e., self to self), associated with the best survival rate2. Syngeneic graft (isograft), Between identical twins3. Allograft - between genetically different individuals of the same species4. Xenograft - between two species, Example—transplant of heart valve from pig to human

• Transplantation rejection involves a humoral or cell-mediated host response againstMHC antigens in the donor graft.1. Hyperacute rejection - irreversible reaction occurs within minutes.Pathogenesis1) ABO incompatibility or action of preformed anti-HLA antibodies in the recipient directed against donor antigens in vascular endothelium2) Type II hypersensitivity reaction (pathologic finding: vessel thrombosis)Example—blood group A person receives a blood group B heart.2. Acute rejection, most common transplant rejection; reversible reaction that occurs within days to weeks1) Type IV cell-mediated hypersensitivity:(a) Host CD4 T cells release cytokines, resulting in activation of host macrophages, proliferation of CD8 T cells, and destruction of donor graft cells.(b) Extensive interstitial round cell lymphocytic infiltrate in the graft, edema, and endothelial cell injury2) Antibody-mediated type II hypersensitivity reaction:(a) Cytokines from CD4 T cells promote B-cell differentiation into plasma cells,producing anti-HLA antibodies that attack vessels in the donor graft.(b) Vasculitis with intravascular thrombosis in recent grafts(c) Intimal thickening with obliteration of vessel lumens in older grafts3. Chronic rejection, irreversible reaction that occurs over months to yearsPathogenesis: not well characterized, involves continued vascular injury with ischemia to tissue; blood vessel damage with intimal thickening and fibrosis.

TYPES OF REJECTION

SCHEMATIC REPRESENTATION OF THE EVENTS THAT LEAD TO THE DESTRUCTION OF HISTOINCOMPATIBLE GRAFTS.

In the direct pathway, donor class I and class II antigens on antigen-presenting cells in the graft (along with B7 molecules, not shown) are recognized by CD8+ cytotoxic T cells and CD4+ helper T cells, respectively, of the host. CD4+ cells proliferate and produce cytokines that induce tissue damage by a local delayed hypersensitivity reaction and stimulate B cells and CD8+ T cells. CD8+ T cells responding to graft antigens differentiate into cytotoxic T lymphocytes that kill graft cells. In the indirect pathway, graft antigens are displayed by host APCs and activate CD4+ cells, which damage the graft by a local delayed hypersensitivity reaction. The example shown is of a kidney allograft.

Craft-versus-Host (GVH) reaction1. Causes a. Potential complication in bone marrow (85% of Cases) and liver transplants b. Potential complication in blood transfusions given to patients with a T-cell• immunodeficiency and newborns2. Pathogenesis a. Donor cytotoxic T cells recognize host tissue as foreign b. Proliferate in host tissue and produce severe organ damage3. Clinical findings a. Bile duct necrosis (jaundice) b. Gastrointesitnal mucosa ulceration (bloody diarrhea) c. Dermatitis4. Treatment Treat with anti-thymocyte globulin or monoclonal antibodies before

grafting Cyclosporine reduces the severity of the reaction.

TYPES OF SOME TRANSPLANTSTYPE OF TRANSPLANT COMMENTS

Cornea Best allograft survival rateDanger of transmission of Creulzfeldt-Jakob disease

Kidney Belter survival with kidney from living donor than from cadaver

Bone marrowCraft contains pluripotential cells that repopulate host stem cellsHost assumes donor ABO groupDanger of graft-versus-host reaction and cytomegalovirus infection

LITERATURE Robbins and Cotran Pathologic Basis of Disease 9th edition./ Kumar, Abbas, Fauto. – 2013.

– Chapter 4. Robbins and Cotran Pathologic Basis of Disease 8th edition./ Kumar, Abbas, Fauto. – 2007.

– Chapter 7. General and clinical pathophysiology. Edited by prof. A.V. Kubyskin. Simferopol. – 2011. Essentials of Pathophysiology: Concepts of Altered Health States (Lippincott Williams &

Wilkins), Trade paperback (2003) / Carol Mattson Porth, Kathryn J. Gaspard. Chapter 10. Pathophysiology, N.K. Symeonova. Kyiv, AUS medicine Publishing. – 2010. Copstead Lee-Ellen C. Pathophysiology / Lee-Ellen C. Copstead, Jacquelyn L. Banasic //

Elsevier Inc. – 2010. Pathophysiology, Concepts of Altered Health States, Carol Mattson Porth, Glenn Matfin.–

New York, Milwaukee. – 2009. Silbernagl S. Color Atlas of Pathophysiology / S. Silbernagl, F. Lang // Thieme. Stuttgart.

New York. – 2000.

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