Transcript Diseases of the Immune System

Diseases of the Immune System
Too little or Too much
The normal Immune response
• Innate immunity
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Epithelial barriers
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Phagocytic cells (monocytes and neutrophils)
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Dendritic cells (type 1 IF)
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Natural killer cells
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Plasma proteins ( including the complement
system)
• Adaptive Immunity
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Humoral – extracellular microbes and their toxins
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Cell-mediated - intracellular microbes
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Components of the Immune system
• Cells
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Lymphocytes- heterogeneous and specialized
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B lymphocytes – Antibody secretion
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CD4+ helper T lymphocytes – activation of
macrophages
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inflammation
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stimulation of B cells
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DC8+ cytotoxic T lymphocytes – killing of
infected cell
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Naïve  effector or memory cells
T Lymphocytes
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Precursors in the thymus
60-70% blood lymphocytes
T cell zones of the peripheral lymphoid organs
Recognizes a specific cell-bound antigen by means of an antigenspecific T cell receptor (TCR)
Alpha and Beta polypeptide chains
Variable (antigen-binding) region and constant region
TCR recognizes peptide antigens that are displayed by MHC
molecules on the surfaces of antigen-presenting cells (MHC
restriction)
Presence of rearranged TCR genes is a marker of T-lineage cells
(mediated by RAG)
Analysis of antigen receptor gene rearrangements is a valuable
assay for detecting lymphoid tumors
T Lymphocytes
• Gamma –delta TCR recognize molecules (peptides, lipids,
small molecules) without MHC display, epithelial surfaces,
function unknown
• NK-T cells recognize glycolipids displayed by CD1 ( MHC-like
molecule) – function unknown
• CD4 – expressed on 60% lymphocytes, cytokine-secreting
helper cells that help macrophages and B lymphocytes
fight infections, bind to class I MHC
• CD8 - expressed on 30% lymphocytes, cytotoxic (killer)
cells destrot host cells that are harboring microbes, bind to
class II MHC
• T cells also recognize additional signals by antigen
presenting cells
B Lymphocytes
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Precursors in bone marrow
10-20% circulating lymphocytes
Lymph nodes, spleen, mucosa-associated lymphoid tissue (MALT)
Recognize antigen via the antigen-binding component of the
receptor complex
IgM and IgD present on the surface of all mature naïve B cells
Each B cell receptor has a unique antigen specificity
Analysis of Ig gene rearrangements is ueful for identifying
monoclonal B cell tumors
After stimulation by antigen, B cells develop into plasma cells that
secrete antibodies
Express CR2 or CD21 = receptor for EBV
Dendritic Cells
• Interdigitating dendritic cells – most important APCs in initiating T
cell responses against protein antigens, located under epithelia and
in interstia, express many receptors to respond to microbes ( TLRs
and mannose), in response to microbes are recruited to T cell
zones of lymphoid tissue to present antigens to T Cells, express high
levels of molecules needed to resent antigens to and ativate CD4+
cells
• Langerhan cells – immature dendritic cells in the epidermis
• Follicular dendritic cells – Found in germinal centers, Fc receptors
for IgG and receptors for C3b, trap antigen bound to antibodies or
complement proteins, present antigens to B cells and selecting B
ells with highest affinity for the antigen, increasing the quality of
the antibody produced
Macrophages
• Function as APCs in T cell activation (present
peptide fragments from phagocytosed microbes
and protein antigens to T cells)
• Key effector cells in cell-mediated immunity, t
cells enhance their ability to kill ingested
microbes (eliminate intracellular microbes)
• Participate in the effector phase of humoral
immunioty by phagocytosing and destroying
opsonized microbes
Natural Killer Cells
• 10-15% of peripheral lymphocytes
• Large granular lymphocytes
• Ability to kill a variety of infected or tumor cells without prior
exposure or activation
• Ability to lyse IgG-coated target cells – antibody–dependent cellmediated cytotoxicity (ADCC)
• Functional activity regulated by a balance between signals from
activating and inhibitory receptors
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NKG2D – activators
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Inhibitor receptors recognize self-class I MHC present on all
healthy cells
• Secrete cytokines – interferon- gamma – activates macrophages
• Activity regulated by cytokines – interleukins 2, 12, 15 (2 and 15
stimulate, 12 inhibits)
Tissues of the Immune system
• Generative (primary or central) - T and B cells mature and
become competent, Thymus and bone marrow
• Peripheral (secondary) – Lymph nodes, spleen, mucosal and
cutaneous lymphoid tissues; organized to concentrate
antigens, APCs, and lymphocytes to optimize interactions
and develop responses
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Paracortex in nodes or periarteriolar lymphoid
sheaths in spleen– T cells
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Follicles – B cells ( germinal centers)
• Lymphocytes constantly recirculate between tissues and
home to particular sites (T cells rome while plasma cells
secrete antibodies that rome)
Major histocompatibility Complex
(MHC) molecules
• Peptide display system of adaptive immunity
• Discovered as products of genes that evoke rejection of
transplanted organs
• Physiologic function is to display peptide fragments of
proteins for recognition by antigen-specific T cellls
• Chromosome 6 – major histocompatibility complex or
human leukocyte antigen (HLA) complex
• Three groups
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Class I MHC molecules
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Class II MHC molecules
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Genes that encode complement components, TNF and
lymphotoxin
MHC Molecules
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Class I
Expressed on all nucleated cells and platelets
HLA-A, HLA-B, HLAC
Display peptides that are derived from proteins, such as viral antigens, that
are located in the cytoplasm and usually produced in the cell, recognized by CD8+
cells
Class II
HLA-D : HLA-DP, HLA-DQ, HLA-DR
Present antigens that are internalized into vesicles, and are typically derived
from extracellular microbes and soluble proteins
HLA haplotype – combination of HLA alleles in each individual, polymorphism, no
two individuals except identical twins are likely to express the same MHC
molecules, leading to graft rejection, associated with inflammatory diseases,
autoimmune diseases, inherited errors of metabolism (e.g. ankylosing spondylitis
and HLA-B27)
Autoimmune diseases and DR locus; 21-hydroxylase HLA-BW47, Hereditary
hemochromatosis HLA-A
Cytokines
• Messenger molecules of the immune system
• Interleukins – mediate communications between
leukocytes
• Cytokines of innate immunity – produced rapidly
in response to microbes and other stimuli; made
by macrophages, dendritic cells, NK cells
• Cytokines of adaptive immunity – produced by
CD4+ cells
• Colony-stimulating factors – cytokines that
stimulate hematopoiesis
Overview of Lymphocyte Activation
and Immune Responses
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Display and recognition of antigens
Clonal selection hypothesis:
Lymphocytes specific for a large number of antigens exist before exposure to the
antigen, and when an antigen enters, it selects the specific cells and activates them.
Cell-mediated Immunity: Activation of T cells and elimination of intracellular microbes
Some of the progeny of the expanded T cells differentiate into effector cells that can
secrete different sets of cytokines, and thus perform different functions
TH1 – Macrophage activation, stimulation of IgG, intracellular microbes,
role in chronic inflammatory diseases (IFN gamma)
TH2 – Mast cell and eosinophil activation, stimulation of IgE, parasites,
allergies
(IL-4 and 5)
TH17 – Recruitment of neutrophils and monocytes, extracellular bacteria,
fungi,
role in chronic inflammatory diseases
(IL-17)
Overview of Lymphocyte activation
• Humoral immunity: Activation of B cells and elimination of
extracellular microbes
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Activated B cells become plasma cells and secrete
antibodies
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Neutralization of microbes and toxins
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Opsonization and phagocytosis
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Antibody-dependent cytotoxicity
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Lysis of microbes
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Complement activation
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Inflammation
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Hypersensitivity Disorders
• General features
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Both exogenous and endogenous antigens may
elicit hypersensitivity reactions
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The development of hypersensitivity diseases (
both allergic and autoimmune disorders) is often
associated with the inheritance of particular
susceptibility genes
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Hypersensitivity reflects an imbalance between the
effector mechanisms of immune responses and the
control mechanisms that serve to normally limit such
responses
Hypersensitivity Disorders
• Type I – immediate hypersensitivity, TH2 cells, IgE , mast cells,
release of mediators that act on vessels and smooth muscle and
pro-inflammatory cytokines that recruit inflammatory cells
• Type II – antibody-mediated.,IgG and IgM participate directly in
injury to cells by promoting their phagocytosis or lysis and injury to
tissues by inducing inflammation, interfere with cellular functions
• Type III – immune complex-mediated, IgG and IgM bind antigens
usually in the circulation, antibody-antigen complexes deposit in
tissues and induce inflammation, leukocytes produce tissue damage
by release of lysosomal enzymes and generation of free radicals
• Type IV – cellular-mediated, TH1 and TH17 and CTLs cause cellular
and tissue injury
Type I Hypersensitivity
• Rapid immunologic reaction occurring within minutes after the
combination of an antigen with antibody bound to mast cells in
individuals previously sensitized to the antigen
• Often called allergy
• Systemic or local
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Immediate or initial - vasodilatation, vascular leakage, smooth
muscle spasm,
glandular secretions, 5-30 minutes start, 60
minutes subsides
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Late-phase - starts 2-24 hours, last s up to several days,
infiltration of tissues with eosinophils, neutrophils, basophils,
monocytes, and CD4+ cells as
well as tissue damage
Type I hypersensitivity
• Mast Cells
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Widely distributed in tissues, especially near blood
vessels, nerves, subepithelial
tissues
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Activated by cross-linking of high-affinity IgE Fc
receptors
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Also triggered by other stimuli -C5a and C3a –
anaphylatoxins, some
chemokines,drugs such as
morphine and codeine, adenosine, mellitin ( in
bee
venom), physical stimuli (heat, cold, sunlight)
• Basophils
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Similar to mast cells, not normally present in tissues,
not as well understood
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Type I Hypersensitivity
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Preformed mediators
Vasoactive amines – most important histamine
Enzymes – primary tissue damage or by generating kinins or activating complement
Proteoglycans – heparin and chondroitin sulfate – package and store amines in granules
Synthesized mediators –
Lipid mediators – Activation of phospholipase A  arachidonic acid
Leukotrienes – C4 and D4 - most potent vasoactive and spasmogenic agents
known
Prostaglandin D2- intense bronchospasm and increased mucus secretion (most
abudnant)
Platelet –activating factor – platelet aggregation, release of histamine,
bronchospasm,increased vascular permeability,
vasodilation,
chemotactic for neutrophils and eosinophils
(not an arachidonic acid
derivative)
Cytokines – TNF, interleukins, chemokines
Type I Hypersensitivity
• The development of immediate hypersensitivity is dependent on
the coordinated actions of a variety of chemotactic, vasoactive, and
spasmogenic compounds
• The recruited cells especially eosinophils amplify and sustain the
inflammatory response without the additional exposure to the
triggering antigen
• Susceptibility to immediate hypersensitivity is genetically
determined
• Atopy
• Hygiene hypothesis
Type I hypersensitivity
• Summary
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Complex disorder resulting from IGE –mediated triggering of mast
cells and subsequent accumulation of inflammatory cells at sites of
antigen deposition. These event are regulated mainly by the induction of
TH 2 helper T cells that stimulate production of IgE ( which promotes mast
cell activation), cause accumulation of inflammatory cells (particularly
eosinophils), and trigger secretion of mucus. The clinical features result
from release of mast cell mediators as well as eosinophil-rich
inflammation.
• Systemic anaphylaxis
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Itching, hives, skin erythema
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Contraction of respiratory bronchioles and respiratory distress
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Laryngeal edema, hoarseness, obstruction
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Vomiting, abdominal cramps
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Shock
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Death
Type II hypersensitivity
• Caused by antibodies that react with antigens present
on cell surfaces or in the extracellular matrix
• Injury caused by:
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Opsonization and phagocytosis – transfusion
reactions, hemolytic disease of the newborn,
autoimmune hemolytic anemia. Agranulocytosis,
thrombocytopenia, certain drug reactions
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Complement and Fc receptor mediated
inflammation –glomerulonephritis, vascular rejection
in tissue grafts
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Antibody-mediated cellular dysfunction –
myasthenia gravis , Graves disease
Type III hypersensitivity
• Antigen-antibody complexes produce tissue damage by eliciting
inflammation at the sites of deposition
• Systemic (e.g. acute serum sickness)
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Formation of antigen-antibody complexes in the circulation
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Deposition of the immune complexes in various tissues – particularly
joints and
glomeruli (high pressure tissues)
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Inflammatory reaction at the sites of deposition – fibrinoid necrosis,
granular
lumpy deposits on immunofluorescence microscopy
• Local ( Arthus Reaction)
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Localized area of tissue necrosis resulting from acute immune
complex vasculitis
usually in the skin
• Acute Serum Sickness
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Type IV hypersensitivity
• Delayed-type hypersensitivity and immune inflammation (
CD4+ cells, TH1, TH17)
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The cellular events in T cell-mediated hypersensitivity
consists of a series of reactions in which cytokines play
important roles (IFNgamma from Th1 and IL17 from Th17
activate macrophages and neutrophils as well as promoting
more cytokine secretion)
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E.g. tuberculin reaction (PPD) -> may become
granuloma, contact dermatitis
• T cell-mediated cytolysis ( CD8+ cells)
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preformed mediators – perforins and granzymes
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E.g. Type I DM, Graft rejection, viral infections
Autoimmune Diseases
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General principles
Autoimmunity –immune reactions against self-antigens
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Organ-specific or systemic
Immune tolerance
Unresponsiveness to an antigen as a result of exposure of
lymphocytes to
that antigen
Self-tolerance – lack of responsiveness to an individual’s own
antigens
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Central tolerance – immature self-reactive t and B cells clones that
reognize
self antigens during their maturation in the
thymus or bone marrow
are killed or rendered harmless
Thymus – AIRE gene, negative selection or deletion,
change to regulatory T cells
BM – receptor editing
Autoimmune Diseases
• Peripheral tolerance
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Anergy – prolonged or functional inactivation
of lymphocytes, CTLA-4 or PD-1 genes
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Suppression by regulatory T cells – CD25
Foxp3 gene, Il-2 receptor gene
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Deletion by activation-induced cell death –
death by apoptosis (Bcl/Bim pro-apototic factor
or FasL-Fas system)
• Immune-privileged sites – testis, eye, brain
Autoimmune Diseases
• Autoimmunity arises from a combination of the inheritance of susceptible
genes, which may contribute to the break-down of self-tolerance, and
environmental triggers, such as infections and tissue damage, which
promote the activation of self-reactive lymphocytes
• Most autoimmune diseases are complex multigenic disorders (HLA/MHC )
• PTPN-22 is said to be the gene from frequently implicated in
autoimmunuty
• Role of infections – induction of costimulators on APCs, molecular mimicry
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but may protect against some autoimmune diseases (because
incidence of autoimmunie disease is higher in countries with fewer
infections)
• Amplification mechanisms exacerbate injury
• Epitope spreading
• Collagen vascular diseases – systemic autoimmune diseases that tend to
involve the blood vessels and connective tissue
Systemic Lupus Erythematosus (SLE)
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Prototype of a multisystem disease of autoimmune origin
Vast array of autoantibodies ( particularly antinuclear antobodies)
immunofluorescense test is sensitive but not specific
antibodes to dsDNA and SM antigen are diagnostic
Criteria for classification of SLE
Malar rash, discoid rash, photosensitivity, oral ulcers
Arthritis, serositis – pleuritis or pericarditis
Renal disorder – proteinuria or RBC casts
Neurological disorder – seizures or psychosis
Hematologic – Hemolytic anemia or cytopenias
Immunological disorder – positive antobodies other than ANA
(antiphospholipid antibodies to phospholipid B2 glycoprotein -> may give false
positive in syphilis serology)
ANA
( 4 or more of the above 11 criteria makes the diagnosis)
SLE
• Antinuclear antibodies
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Antibodies to DNA
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Antibodies to histone
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Antibodies to nonhistone proteins bound to RNA
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Antibodies to nucleolar antigens
• Patterns of nuclear fluorescence
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Homogeneous or diffuse nuclear staining – histone,
chromatin, double-stranded
DNA
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Rim or peripheral staining – double-stranded DNA
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Speckled – least specific, non-DNA nuclear
constituents: Sm, RNP, SS-A ,SS-B
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Nucleolar – RNA
SLE
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ANA
Sensitive – Positive in virtually every patient with SLE
Not specific – Also positive in other auto-immune diseases and in 5-15% of
normal individuals
Antibodies to Smith antigen and ds-DnA are virtually diagnostic of SLE (HLA-DQ)
40-50% have antiphospholipid antibodies – lupus anticoagulant, hypercoaguable
state
False positive RPR (syphilis serology)
Cause of SLE is unknown
Model for pathogenesis
UV irradiation and other environmental insults lead to apoptosis of cells
Large burden of nuclear antigens because not adequately cleared  Selfreactive lymphocytes (because of defective tolerance) stimulated by these self
nuclear antigens and antibodies are produced Cycle of antigen release and
immune activation  Production of high-affinity autoantibodies
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Mechanisms of tissue injury
Most of the visceral lesions are caused by immune complexes (Type III
hypersensitivity)
Autoantibodies specific for RBCs, WBCs, platelets opsonize these cells and
promote their phagocytosis and lysis
Clinical manifestations
Hematologic 100%
Arthritis, skin – 80-90%
Fever, fatigue, weight loss
Renal
Neuropsychiatric, peripheral neuropathy
Pleuritis, pericarditis
Myalgia
GI
Ocular
Raynaud phenomenon
SLe
• Renal (granular deposits in all)
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Class I Minimal mesangial (no glomerular capillary involvement)
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Class II Mesangial proliferative (no glomerular capillary
involvement)
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Class III Focal proliferative (<50% of all glomeruli; wire loop lesion)
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Class IV Diffuse proliferative ( most severe) (entire glomerulus; >50%
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all glomeruli; wire loop lesion)
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Class V Membranous (thickening of capillary wall and nephrotic
syndrome)
• Libman-Sacks endocarditis – nonbacterial verrucous
• Most common causes of death – renal failure and intercurrent infections
Other forms of Lupus
• Chronic Discoid LE
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Skin manifestations without systemic usually
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Positive ANA but usually not anti-ds-DNA antibodies
• Subacute cutaneous LE
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Skin lesions widespread, superficial and not scarring
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mild systemic symptoms
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anti- SS-A antibodies
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HLA-DR3
• Drug-induced LE ( e.g. hydralazine, procainamide)
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Positive ANA
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No renal or CNS involvement
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anti-histone antibodies
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HLA-DR4
Sjogren Syndrome
• Dry eyes (keratoconjunctivitis sicca)
• Dry mouth (xerostomia)
• Destruction of lacrimal and salivary glands – lymphocytic infiltration and
fibrosis
• Often associated with other autoimmune disorders RA, increased risk of
B-cell lymphoma
• Anti–SS-A ( Ro) and anti-SS-B (La) antibodies
• Diagnosis - biopsy of the lip (to examine minor salivary glands)
• Clinical – blurring of vision, burning and itching, thick secretions; difficulty
swallowing dry foods, decreased taste, cracks and fissures in mouth,
dryness of mucosa; parotid gland enlargement; dryness of nasal mucosa,
epitaxis; bronchitis, pneumonitis; tubulointerstitial nephritis
• Mikulicz syndrome – lacrimal and salivary gland enlargement from any
cause
Systemic Sclerosis (Scleroderma)
• Chronic inflammation, widespread damage to small blood vessels,
progressive interstitial and perivascular fibrosis in the skin and
multiple organs
• Diffuse vs limited scleroderma
• CREST syndrome – calcinosis, Raynaud phemomenon, esopahgeal
dysmotility, sclerodactyly, telangiectasia
• Anti-Scl 70 antibody (DNA topoisomerase I) -> pulmonary fibrosis
• Anticentromere antibody -> CREST syndrome
• Microvascular disease may be the initial lesion
• Mixed connective tissue disease – features of SLE, scleroderma, and
polymyosits; antobodies to RNP (U1 )
Rejection of Tissue transplants
• Complex process in which both cell-mediated
immunity and circulating antibodies play a role.
• T cells
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Cellular rejection
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Direct pathway – T cells recognize allogeneic
MHC molecules on the
surface of APCs in
the graft, major pathway in acute cellular
rejection CD8 CTL and CD4
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Indirect pathway – T cells recognize MHC
antigens after they are
presented by the
recipient’s APCs, more important in chronic
rejection CD4 only
Rejection of tissue transplants
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Antibody-mediated rejection
Hyperacute rejection
Preformed antidonor antibodies are present in the circulation
Currently screening by cross-matching has made this an insignificant clinical problem
Acute humoral rejection
Target the graft vasculature leading to rejection vasculitis
Antibodies to class I and class II MHC antigens from the donor graft
Acute cellular rejection
CD4+ and CD8+; causing endothelitis
Chronic Rejection
Fibrosis and sclerosis of arteries
Renal transplants
Rise in serum creatinine over 4-6 months signals chronic rejection
Hematopoietic transplants
Graft vs Host disease
Acute – immune system, skin, intestines, liver
Chronic – systemic sclerosis pitcture
Immunodeficiency
Primary Immunodeficiency syndromes
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X-linked agammaglobulinemia (Bruton’s agammaglobulinemia)
Failure of B cell precursors to develop into mature B cells
Mutation in Bruton tyrosine kinase gene
X-linked
Becomes clinically apparent after 6 months of age when maternal
immunoglobulins are depleted
Recurrent bacterial infections of the respiratory tract: (H.flu, Strep pneumo,
Staph aureus)
Enteroviruses, giardia
B cells are absent or marked decreased in the circulation
Serum levels of all immunoglobulins are depressed
Pre-B cells with B lineage marker CD19, but not membrane Ig, are found in
normal numbers in the bone marrow
Germinal centers of lymph nodes, Peyer’s patches, appendix and tonsils are
underdeveloped
Plasma cells are absent
T cell-mediated immunity is normal
Primary Immunodeficiency syndromes
• Common variable immunodeficiency
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Near or near-normal B cell counts
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Clinical manifestations similar to Bruton but onset later in
childhood or
adolescence
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Hyperplastic B cell areas – B cells can proliferate but not
produce antibodies so
no feedback
• Isolated IgA deficiency
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Low levels of secretory IgA
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Recurrent sinopulmonary infections and diarrhea
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Severe reaction to blood transfusions containing IgA
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Some also have deficiency of IGG2 and IgG4 subclasses
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Primary Immunodeficiency Syndromes
• Hyper-IgM Syndrome
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Make IgM antibodies but are deficient in their
ability to make IgG, IgA, and IgE
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Recurrent pyogenic infections, some also get
pneumocystis
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70% x-linked, 30% AR
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Defect affects the ability of helper T cells to deliver
activating signals to B cells
and macrophages
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Mutation in gene encoding CD40 or activationinduced deaminase
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Primary Immunodeficiency Syndrome
• DiGeorge Syndrome
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T cell deficiency resulting from failure of
development of the third and fourth
pharyngeal pouches
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Hypocalcemia, CHD
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22q11 deletion syndrome
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Abnormal facies
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Fungal and viral infections
Primary Immunodeficiency Syndromes
• SCID
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Both humoral and cell-mediated immune responses
are affected
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Infants present with thrush, diarrhea, FTT, morbilliform
rash (GVH)
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Susceptible to wide range of infections, die by one year
of age without bone
marrow transplantation
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X-linked 50-60% - mutation in the common gamma
chain of cytokine receptors
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AR - most have deficiency of ADA
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Gene therapy has been tried ( large % developed acute
t cell leukemia)
Primary Immunodeficiency Syndrome
• Wiskott-Aldrich syndrome
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X-linked recessive
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Thrombocytopenia, eczema, marked vulnerability to
recurrent infection
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Mutation in WASP gene
• Complement deficiencies
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C2 – increased incidence of SLE
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C3 – increased incidence of recurrent serious pyogenic
infections and imunecomplex GN
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C5-9 – increased incidence of Neisseria infections
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C1 inhibitor – hereditary angioedema
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Acquired Immunodeficiency Syndrome
(AIDS)
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Diseased caused by the retrovirus HIV
Profound immunosuppression leading to opportunistic infections, secondary neoplasms, and
neurologic manifestations
Epidemiology
Homosexual or bisexual men > 50%
IV drug abusers
Hemophiliacs
Recipients of blood transfusions
Heterosexual contacts of members of high-risk groups ( most rapidly growing group)
Unknown in 5%
Major routes of transmission
Sexual transmission
Parenteral transmission
Mother-to-infants
AIDS
• Two major targets of HIV infections
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Immune system
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CNS
• Infection of and loss of CD4+ T cells
• Life cycle of HIV
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Infection of cells
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Integration of the provirus into the host genome
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Activation of viral replication
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Production and release of infectious virus
AIDS
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Infection of cells
The initial step is the binding of the gp120envelope glycoprotein to CD4
molecules  conformational change  new recognition site for
coreceptors ( CCR5 and CXCR4)
Fusion of the virus with the host cell
Virus core containing the HIV genome enters the cytoplasm
Requires HIV binding to coreceptors – implications for resistance to infection
Infects memory and activated T cells, not naïve cells because of enzyme
APOBEC3G that causes mutation in the HIV genome
Viral replication
Reverse transcription  Synthesis of ds-complementary DNA
Quiescent cells - cDNA remains in cytoplasm
Dividing cells - cDNA is incorporated into the host genome
After cell activation - cell lysis
HIV thrives when the host cells and macrophages are physiologically
activated
AIDS
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Mechanism of T cell immunodeficiency in HIV infection
Loss of CD4+ T cells is mainly because of infection of the cells and the direct cytopathic
effects of the replicating virus
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Colonization of the lymphoid tissues by HIV leading to progressive destruction
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Chronic activation of uninfected cells leads to apoptosis ( activation-induced cell death)
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Loss of immature precursors
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Fusion of infected and uninfected cells ( synctia formation)  cell death
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Low –level chronic or latent infection of T cells
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Apoptosis of uninfected cells by binding of the soluble gp120 to the CD4 molecule
Qualitative defects in T cells even in asymptomatic persons
AIDs
• Infection of non- T cells
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Macrophages and dendritic cells
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Important in the pathogenesis of HIV infection
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Gatekeepers and potential reservoirs of infection
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Mucosal dendritic cells are infected by the virus and transport it to
regional lymph
nodes where the virus is transmitted to CD4+ cells
• Despite the presence otfspontaneously activated B cells, patients with
AIDS are unable to mount antibody responses to newly encountered
antigens
• Pathogenesis of CNS involvement
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Macrophages and microglia are the predominant cell types infected
in the brain
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Neurologic deficits caused by viral products and soluable products
from infected microglia ?
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AIDS
• Natural History of HIV infection: Primary infection
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HIV disease begins with acute infection, partly
controlled by the adaptive immune response,
advances to chronic progressive infection of the
peripheral lymphoid tissues
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Early infection is characterized by infection of
memory CD4+ T cells in mucosal lymphoid tissues
and death of many infected cells
AIDs
• Acute retroviral syndrome
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Self-limited acute illness
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Non-specific symptoms – sore throat,
myalgias, fever, weight loss, fatigue
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“Flu-like” picture
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3-6 weeks after infection
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Resolves in 2-4 weeks
• Extent of viremia after the acute infection is a
useful marker of HIV progression ( measured
AIDS
• Chronic infection
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Lymph nodes and spleen are sites of
continuous HIV replication and cell destruction
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Phase of clinical latency
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Asymptomatic or minor opportunistic
infections
• Progression to AIDS
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Breakdown of host defenses
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Dramatic increase in plasma virus
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Severe, life threatening clinical disease –
Serious opportunistic infections, secondary
AIDS
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Defining opportunistic infections and neoplasms
Cryptosporidiosis enteritis
Toxoplasmosis ( pneumonia or CNS)
Pneumocystosis
Candidiasis ( esopahgeal, tracheal, or pulmonary)
Crytococcosis (CNS)
Coccidioidomycosis (disseminated)
Histoplasmosis (disseminated)
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MAC
Nocardiosis
Salmonella
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CMV
HSV
VZV
Progressive multifocal leukoencephalopathy
AIDS
• Tumors
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Kaposi sarcoma ( HHV8 virus)
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AIDS –related lymphomas
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Increased incidence of carcinoma of the
cervix and anal cancer
• CNS
•
Meningoencephalitis
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Aseptic meningitis
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Vacuolar myelopathy
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Peripheral neuropathy
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Progressive encephalopathy – AIDS-dementia
complex
AMyloidosis
• Pathologic proteinaceous substance deposited
in extra cellular spaces in various tissues and
organs in a wide variety of clinical settings
• Continuous nonbranching fibrils
• Most common
•
AL – immunoglobulin light chains (plasma
cell tumors)
•
AA - 76 amino-aid residues ( chronic
inflammatin – secondqry amyloidosis)
•
Beta-amyloid - Alzheimer disease
Amyloidosis
• Primary Amyloidosis ( Immunoyte dyscrasias
with amyloidosis)
•
Bence Jones proteins
• Reactive systemic
• Hemodialysis-associated
• Heredofamilial
• Localized
• Endocrine
• Amyloid of aging – senile systemic