122 DISEASES OF IMMUNITY (PART 2) Cua, Cudia, De Castro, De Guzman, De Veyra PH 122- Diseases of Immunity (Part 2)

Lecturer: Dr. Treah Mae Suacillo Date of Lecture: 13 December 2011

Transcribed by: Cua, Cudia, de Castro, de Guzman, de Veyra 2011

Transcribed by: Aaron Abad, Io Angeles, Dana Arellano, Kayemar Aseron, Aaron Ayro

Immune Deficiency Diseases - may be caused by inherited defects affecting immune system development, or they may result from secondary effects of other diseases such as infection, malnutrition, aging, immunosuppression, autoimmunity, or chemotherapy - increased susceptibility to infections as well as to certain forms of cancer - type of infections depending on affected component of Immune System (IS): o with defects in Ig, complement, or phagocytic cellssuffer recurrent infections with pyogenic bacteria; o with defects in cell-mediated immunity prone to infections caused by viruses, fungi, and intracellular bacteria Immunologic Deficiency Syndromes A. Primary Immunodeficiencies (Congenital) - rare, usually occurs early in life (6months to 2 yrs) because the affected infants are susceptible to recurrent infections - hereditary, affect either adaptive immunity (humoral or cellular) or innate host defense mechanisms, including complement proteins and cells like phagocytes and NK cells -maternal Ab loss - some primary immune deficiencies: X-linked Agammaglobulinemia of Bruton Common Variable Immunodeficiency Isolated IgA Deficiency Hyper-IgM Syndrome DiGeorge Syndrome (Thymic Hypoplasia) Severe Combined Immunodeficiency Diseases (SCID) Immunodeficiency with Thrombocytopenia & eczema (Wiskott-Aldrich Syndrome) Genetic deficiencies of the Complement System B. Secondary Immunodeficiencies - more common than primary immunodeficiencies - may be encountered in patients with malnutrition, infection, cancer, renal disease, or sarcoidosis - most common cases: therapy-induced suppression of the bone marrow and of lymphocyte function. - result from altered immune function due to infection, malnutrition, aging, immunosuppression, irradiation, chemotherapy, autoimmunity - Acquired Immunodeficiency Syndrome (AIDS)

1.

X-linked Agammaglobulinemia of Bruton characterized by the failure of pre-B cells to differentiate into B cellsabsence of gamma globulin in the blood Basic defect is lack of mature B cells -mutation in B cell tyrosine kinase gene (BTK) w/c has a role in signal transduction from antigen receptor complex driving maturation Present with recurrent bacterial infections after 6 months of age (after maternal immunoglobulins are depleted) Absent or markedly decreased numbers of B cells in the circulation, with depressed serum levels of all classes of immunoglobulins (virtually no serum Ig) Most viral & fungal infections are handled (except enterovirus echovirus & poliovirus) bec. Because T-cell-mediated immunity is intact LN & spleen lack germinal centers & plasma cells are absent from all tissues Increased frequency of autoimmune connective tissue disease

2.

Common Variable Immunodeficiency basis of the Ig deficiency is variable Heterogeneous group of disorders, congenital & acquired, sporadic & familial Hypogammaglobulinemia affecting all immunoglobulin classes (occasionally only IgG) Although most patients have normal numbers of mature B cells, plasma cells are absent, suggesting a block in antigen-stimulated B-cell differentiation. Pathogenesis, unclear; Intrinsic B cell defect, defective B cell maturation as a result of T cell defect (deficient T-cell help or excessive Tsuppressor activity), complement genes in HLA Symptoms similar to agammaglobulinemia & start from childhood or adolescence (sa Robbins: 2nd to 3rd decade of life) Prone to autoimmune diseases (hemolytic and pernicious anemia) & lymphoid malignancies

3.

Isolated IgA Deficiency Common immunodeficiency Virtual absence of serum & secretory IgA, occasionally IgG2 & IgG4 Familial or acquired

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122 DISEASES OF IMMUNITY (PART 2) Cua, Cudia, De Castro, De Guzman, De Veyra

Recurrent sinopulmonary & gastrointestinal tract infection (diarrhea) Prone to allergies & autoimmune diseases Basic defect- failure in maturation of IgA positive B cells 40% of cases have antibodies directed against IgA pathogenesis of IgA deficiency seems to involve a block in the terminal differentiation of IgA-secreting B cells to plasma cells; IgM and IgGnormal levels (See Figure 1) 4. Hyper IgM Syndrome - production of IgM but failure to produce IgA, IgE, and IgG antibodies - failure of T cells to cause B cell switching to form immunoglobulins (CD40L interaction) - recurrent bacterial infections - pneumocystis infection (See Figure 2) 5. Digeorge Syndrome - multiorgan congenital disorder - Failure of development of 3rd & 4th pharyngeal pouches before the 8th week of gestation - thymic aplasia/hypoplasia - parathyroid hypoplasia - deletion of gene mapping to 22q11 (See Figure 3) Characteristics of Digeorge Syndrome: - hypertelorism - cleft lip and palate - absent parathyroids and thymus 6. Severe Combined Immunodefienciency Diceases(SCID) - Autosomal or X-linked (50-60%) disorder - Characterized by lymphopenia& defects in T & B cell function - Represents a constellation of genetically distinct sydromes all exhibiting defects in both humoral and cell-mediated immune responses X linked mutation in common chain subunit of cytokine receptors, affect lymphoid progenitor cytokines (IL - 7) severe T cell defect - IL-7 : most important cytokine receptor because it is the factor responsible for stimulating the survival and expansion of immature B and T cell precursors in the bone marrow.
Figure 5

AR(autosomal recessive)caused by deficiency of enzyme adenosine deaminase (accumulation of lymphocyte-toxicmetabolites deoxy ATP) T cell defects lead to secondary B cell defects Hypoplastic lymphoid tissues In the 2 most common forms of SCID, the thymus is hypoplastic; lymph nodes and lymphoid tissues are atrophic and lack B cell germinal centers as well as paracortical T cells Treatment -Bone marrow transplant 1st human dse for which gene therapy was successful (See Figure 4) 7. Immunodeficiency with Thrombocytopenia & eczema (Wiskott-Aldrich Syndrome) - X linked recessive disease - Characterized by thrombocytopenia, eczema, and a marked vulnerability to recurrent infection, ending in early death - Recurrent infections, predilection for lymphoma - Morphologically normal thymus but there is peripheral T cell depletion defect in cellular immunity - Ab responses are variable (poor to polysaccharide antigens) - Defect maps to Xp11.23 (WASP gene) protein product links cell surface receptors & intracellular cytoskeleton - Tx bone marrow transplant

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122 DISEASES OF IMMUNITY (PART 2) Cua, Cudia, De Castro, De Guzman, De Veyra

AIDS - Infectious secondary form of immunodeficiency - Retroviral disease caused by the human immunodeficiency virus (HIV) - Characterized by profound suppression of T cell mediated immunity; opportunistic infections, secondary neoplasms, neurologic disease - HIV transmission: sexual contact, parenteral inoculation, vertical transmission (mother to fetus) - 5 major risks in US: homosexual men/bisexual (traumatized rectal mucosa), intravenous drug users (contaminated needles & paraphernalia), haemophiliacs (factor VIII concentrate prior to 1985), blood component recipients, high-risk heterosexual contact, no risk factor identified in 6% of cases - Risk of seroconversion after accidental needle stick (0.3%) - Outside of US & Europe, most common transmission occurs in male to female (vaginal intercourse) - Transmission is facilitated by STDs with genital ulcerations - Etiologic agent HIV1 human type C retrovirus (animal lentivirus); HIV2 West Africa -Nontransformingcytopathic retrovirus, causing target T cell destruction -HIV-1 lipid envelope derived from infected host membrane is studded with GP 120 & 41 -Viral core contains major capsid protein p24, nucleocapsid protein, genomic RNA, viral enzymes : protease, integrase, reverse transcriptase -Genes present (not seen in other retroviruses) TAT, VPU, VIF, NEF, REV -TAT & REV play a role in transcription HIV Viral genes: 1. Long Terminal Repeat 2. Viral Infectivity Factor 3. Viral Protein U 4. Gp160Envelope Protein 5. Negative Effector (p24) 6. Gag 7. Polymerase 8. Viral Protein R 9. Regulator of Viral Gene Expression (p19) 10. Tat Pathogenesis of HIV: 1. CD4+ helper T cell depletion is the central pathogenic pathway of AIDS, whichis the highaffinity receptor for gp120 protein on HIV-1, as well as other major chemokine coreceptors CCR5, CXCR4

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After binding of gp120 to CD4 & chemokine receptor, gp41 undergoes conformational change allow internalization of virus Genome undergoes reverse transcription & proviral DNA is integrated into the host DNA genome Transcription, translation & viral propagation with T cell activation, in the absence of T cell activation, infection enter a latent phase Infection of lymphoid organs where monocytes/macrophages act a viral reservoirs (transfer virus to T cell on antigen presentation) and also FDC in lymph node ger,oma; centers Membrane Fusion

T cell depletion ensues with cell loss due to intracellular viral replication with subsequent cell lysis (1-2 billion CD4+ T cells are lysed daily) Other modes of T cell loss: Progressive destruction of architecture & cellular composition of lymphoid organs Chronic activation of uninfected cells (responding to infection) leading to activation-induced cell death Fusion of infected & uninfected cells via gp120 Binding of soluble gp120 to noninfected CD4+ T cells leading to apoptosis Consequences of HIV infection: T cell depletion Qualitative defects in T cell function Selective loss of T cell memory Paradoxic polyclonal B cell activation, intrinsic B cell defects

Other Information: CNS is a major target for HIV infection Occurs predominantly by the infected monocytes or macrophages in circulation These infected cells activate or release toxic cytokines directly or recruit other neurondamaging inflammatory cells. Tissue changes are nonspecific except for CNS Natural history: 3 phases: Early acute phase- transient viremia, widespread seeding of lymphoid tissue, CD4+ T cell decrease, seroconversion (sore throat, myalgias, aseptic meningitis, 6-12 weeks, CD4 normalizes Middle chronic phase- Clinical latency, vigorous viral replication in lymphoid tissues, persistent LN

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122 DISEASES OF IMMUNITY (PART 2) Cua, Cudia, De Castro, De Guzman, De Veyra

enlargement, may last for years (7-10 years), fever rash, viremia, (minor symptoms) fatigue in latter part AMYLOIDOSIS Final progression to AIDS- low CD4+ T cells, weight loss, diarrhea, opportunistic infections, secondary neoplasms (full-blown) Systemic disease involving components of the immune system; pathogenesis related to misfolded protein thus producing extracellular deposits of fibrillar protein structure Amyloid- proteinaceous amorphous, eosinophilic, hyaline extracellular substance deposited between cells in various tissues & organs of the body in varied clinical settings, which with progressive accumulation produces atrophy of adjacent cells Aggregation of misfolded forms happens only when its concentration reaches abnormally high levels. This happens as senile amyloidosis - an individual ages increased production (e.g., in chronic inflammatory states) amyloidosis associated with long-term dialysis -impaired excretion of protein hereditary amyloidosis from mutation to form a protein folded improperly and then aggregates amyloidosis associated with Alzheimer disease - limited proteolysis may generate a protein that forms amyloid fibrils Congo red stain - to identify amyloid desposits in tissues; green birefringence of stained amyloid on polarizing microscopy Physical nature- non-branching fibrils, cross pleated sheet conformation Chemical nature- fibril proteins (95%), P component & glycoprotein (5%) 20 biologically distinct forms, 3 most common: AL (amyloid light chain)- plasma cells; complete immunoglobulin (Ig) light chains, amino-terminal fragments of light chains, or both. AA (amyloid associated)- nonimmunoglobulin protein from in liver; associated with chronic inflammatory disorders A amyloid- found in cerebral lesion of Alzheimer disease * A protein - from larger transmembrane glycoprotein called amyloid precursor protein((APP)) Several other proteins have been found in amyloid deposits in a variety of clinical settings Transthyretin (TTR) - normal serum protein; binds&transports thyroxine and retinol

Classification Categories of HIV Infection

Clinical features of full-blown AIDS - Opportunistic infections

(See Table 2) - Widespread Pyogenic bacterial infections - Malignant neoplasms Kaposi sacroma( most common ) - monoclonal spindle cell neoplasm with prominent vascular component associated with HHV-8(human herpesvirus type 8) - far more common among homosexual or bisexual males - multicentric and tend to be more aggressive; they can affect the skin, mucous membranes, gastrointestinal tract, lymph nodes, and lungs. Aggressive B cell Non-Hodgkin lymphomas (Burkitt, immunoblastic)- EBV related, brain involvt (2nd most common) Invasive cancer of uterine cervix - human papillomavirus (HPV) related that is seen in immunocompromised patients Clinical neurologic involvement (40-60%) sole or earliest presenting feature of HIV infection Most common- progressive encephalopathy (AIDS dementia complex) Acute aseptic meningitis Vacuolar myelopathy Peripheral neuropathy

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122 DISEASES OF IMMUNITY (PART 2) Cua, Cudia, De Castro, De Guzman, De Veyra

mutant lysozyme.2-microglobulin component of the MHC class I molecules and a normal serum protein, is an amyloid fibril subunit (A2m)

Minor components always present in amyloid: Serum amyloid P component, proteoglycans, highly sulfated glycosaminoglycans Amyloid deposition may be systemic or localized Clinically classified as primary (immunocyte dyscrasia), secondary (complication of underlying chronic inflammatory dse.) hereditary or familial (distinct pattern of organ involvement) * gene for familial Mediterranean fever cloned and its product is called pyrin(regulating acute inflammation &presumably by inhibition of neutrophils) *plasma cells may synthesize&secrete either or light chain(Bence Jones proteins)

(See Table 3) Morphology is not consistent or distinctive but there are generalizations: - Secondary inflammation yields most severe systemic involvements - Commonly involve the kidney*, liver, spleen, lymph nodes, adrenals, thyroid - Organs involved are enlarged, firm & waxy - 8Kidney involvement is most common & most severe, primarily in glomeruli - Sago spleen(tapioca like granules) deposition limited to follicles alone - Lardaceous spleen- sinuses & red pulp of spleen - Liver- sinuses, space of Disse, parenchyma, Kupffer cells - Heart- major organ in senile systemic amyloidosis, subendocardial & myocardial - Other common organs: adrenals, thyroid, pituitary, GIT, tongue, respiratory tract, nerves

Figure 6

A, A section of the liver stained with Congo red reveals pink-red deposits of amyloid in the walls of blood vessels and along sinusoids. B, Note the yellow-green birefringence of the deposits when observed by polarizing microscope. (Courtesy of Dr. Trace Worrell and Sandy Hinton, Department of Pathology, University of Texas Southwestern Medical School, Dallas, Texas.)

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122 DISEASES OF IMMUNITY (PART 2) Cua, Cudia, De Castro, De Guzman, De Veyra

Figure 1

Figure 2

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122 DISEASES OF IMMUNITY (PART 2) Cua, Cudia, De Castro, De Guzman, De Veyra

Figure 3

Figure 4

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122 DISEASES OF IMMUNITY (PART 2) Cua, Cudia, De Castro, De Guzman, De Veyra

Table 2
PROTOZOAL AND HELMINTHIC INFECTIONS Cryptosporidiosis or isosporidiosis (enteritis) - persistent diarrhea(common in patients with AIDS) Pneumocystosis (pneumonia or disseminated infection) by Pneumocystis jiroveci Toxoplasmosis (pneumonia or CNS infection)- most common secondary infection of the CNS FUNGAL INFECTIONS Candidiasis (esophageal, tracheal, or pulmonary) Cryptococcosis (CNS infection) Coccidioidomycosis (disseminated) Histoplasmosis (disseminated) BACTERIAL INFECTIONS Mycobacteriosis ("atypical," e.g., Mycobacterium avium-intracellulare, disseminated or extrapulmonary; M. tuberculosis,pulmonary or extrapulmonary) *M. tuberculosis manifests itself early in the course of AIDS * infections with atypical mycobacteria are seen late in the course of HIV disease; patients with fewer than 100 CD4+ cells/L Nocardiosis (pneumonia, meningitis, disseminated) Salmonella infections, disseminated VIRAL INFECTIONS Cytogegalovirus (pulmonary, intestinal, retinitis, or CNS infections) Herpes simplex virus (localized or disseminated) Varicella-zoster virus (localized or disseminated) Progressive multifocal leukoencephalopathy

Table 3

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