14,15

Pathology of the immune
response. Hypersensitivity
reactions. Autoimmune diseases.

response. Immunologic
deficiency syndromes.
Transplantation immunity

Questions
 Immunity. Types. Morphological basis.
 Pathological immune reactions.
Autoimmune diseases.
 Immunologic deficiency syndromes –
primary and secondary.
 Transplantation immunity. Reaction of
transplant rejection.

Immunity
 INNATE (present before birth,
“NATURAL”)
 ADAPTIVE (developed by exposure to
pathogens, or in a broader sense,
antigens)

Innate (natural, nonspecific)
immunity
 Antigen-independent cells providing first
defense against pathogens
 Types of cells
 Phagocytic cells (e.g., neutrophils,
macrophages)
 Natural killer cells

INNATE IMMUNITY
 Barriers
 Cells
 lymphocytes, macrophages, plasma cells, NK
cells
 Cytokines/chemokines
 Plasma proteins
 Complement, Coagulation Factors
 Toll-like receptors (TLR’s)

Acquired (specific) immunity
 Antigen-dependent activation and expansion of
lymphocytes

cellular
 T cells are involved in cell-mediated immune
responses to antigens

humoral
 B lymphocytes produce antibodies

Cells of the Immune System
 LYMPHOCYTES, T
 LYMPHOCYTES, B
 PLASMA CELLS (modified B cells)
 MACROPHAGES (“HISTIOCYTES”)
 Antigen Presenting Cells (APCs)
 “DENDRITIC” CELLS
 Antigen Presenting Cells (APCs)
 NK (NATURAL KILLER) CELLS

Cells of the Immune System
Cell Type Derivation Location Function
T cells
CD4 (helper)
CD8
(cytotoxic
/suppressor)
Bone marrow
lymphocyte
stem cells mature in
thymus
Peripheral blood and bone
marrow, thymus,
paracortex of lymph
nodes, Peyer's patches
CD4 cells: secrete cytokines (IL-2 →
proliferation of CD4/CD8 T cells; γ-interferon
→ activation of macrophages); help B cells
become antibody-producing plasma cells
CD8 cells: kill virus-infected, neoplastic, and
donor graft cells
B cells Bone marrow stem
cells
Peripheral blood and bone
marrow, germinal follicles
in lymph nodes, Peyer's
patches
Differentiate into plasma cells that produce
immunoglobulins to kill encapsulated bacteria
(e.g., Streptococcus pneumoniae)
Act as APCs that interact with CD4 cells
Natural killer
cells
Bone marrow stem
cells
Peripheral blood (large
granular lymphocytes)
Kill virus-infected and neoplastic cells
Macrophages Conversion of
monocytes into
macrophages in
connective tissue
Connective tissue; organs
(e.g., alveolar macrophages,
lymph node sinuses)
Involved in phagocytosis and cytokine
Production
Act as APCs
Dendritic cells Bone marrow stem
cells
Skin (Langerhans' cells),
germinal follicles
Act as APCs

1) ROUND NUCLEUS
2) OVOID CYTOPLASM
3) PERIPHERAL CHROMATIN
4) “CLEAR ZONE” BETWEEN NUCLEUS AND WIDER LIP OF
CYTOPLASM
PLASMA CELLS

Lymph nodes and spleen-
lymphocytes B and T location

MACROPHAGES are
MONOCYTES that have come
out of circulation and have
gone into tissue

Dendridic cells
 A type of
macrophage with
many spiny
cytoplasmic
processes, found in
many places
 skin (Langhans cells)
 brain (microglia)
 They are also
APC’s.

Natural killer cells (NK cells)
 A type of cytotoxic lymphocyte
 a major component of the innate
immune system
 NK cells play a major role in the
rejection of tumors and cells
infected by viruses.
 The cells kill by releasing
small cytoplasmic granules of
proteins (perforin and granzyme)
 that cause the target cell to die by
apoptosis.

General scheme of cellular events
 APCs (Macrophages, Dendritic Cells)
 T-Cells (Control Everything)
 CD4 “REGULATORS” (Helper)
 CD8 “EFFECTORS”
 B-Cells Plasma Cells AB’s
 NK Cells

CYTOKINES
 Proteins produced by many cells -Ly and
macrophages
 Numerous roles in acute and chronic inflammation,
and immunity
 mediate innate (natural) immunity

IL-1, TNF, Interferons
 regulate lymphocyte growth

many interleukins, ILs
 activate inflammatory cells
 stimulate hematopoesis,

Colony Stimulating Factors, CSFs

MHC
Major Histocompatibility Complex
 A genetic “LOCUS” on Chromosome 6, which
codes for cell surface compatibility
 Also called HLA (Human Leukocyte Antigens)
in humans and H-2 in mice
 It’s major job is to make sure all self cell
antigens are recognized and “tolerated”,
because the general rule of the immune system
is that all UN-recognized cells will NOT be
tolerated

Major Histocompatibility Complex
(MHC)
 Location
 Short arm of chromosome 6
 Human leukocyte antigen (HLA)
genes
 Code for HLA proteins that are
unique to each individual
 HLA association with disease
 HLA-B27 with ankylosing
spondylitis
 HLA-DR2 with multiple sclerosis
 HLA-DR3 and -DR4 with type 1
diabetes mellitus
Class I MHC molecules
 Coded by HLA-A, -B, and -C
genes
 Present on the membranes of
all nucleated cells
 Not present on mature RBCs;
present on platelets
 Recognized by CD8 T cells and
natural killer cells
Class II MHC molecules
 Coded by HLA-DP, -DQ, and
-DR genes
 Present on antigen-presenting
cells (APCs)
 B cells, macrophages, dendritic
cells
 Recognized by CD4 T cells

MHC MOLECULES
(Gene Products)
I (All nucleated cells and platelets), cell surface
glycoproteins, ANTIGENS
II (APC’s, i.e., macs and dendritics, lymphs),
cell surface glycoproteins, ANTIGENS
III Complement System Proteins

IMMUNE SYSTEM DISORDERS
 HYPERSENSITIVITY REACTIONS
 I-IV types
 “AUTO”-IMMUNE DISEASES
 “collagen” diseases
 IMMUNE DEFICIENCY SYNDROMES:
 primary (genetic)
 secondary (acquired)

Hypersensitivity Reactions
 Pathologic or excessive reactions against an antigen are manifestations of
"hypersensitivity
 May result from various underlying abnormalities
 Autoimmunity
 Reactions against microbes

Str., tbc
 Reactions against environmental antigens

pollens, animal danders, or dust mites
 Chronic inflammation, is the major component of the pathology of these
disorders
 immune-mediated inflammatory diseases

 I (Immediate Hypersensitivity)
 II (Antibody Mediated Hypersensitivity)
 III (Immune-Complex Mediated
Hypersensitivity)
 IV (Cell-Mediated Hypersensitivity)

Reaction Pathogenesis Examples
Type I IgE-dependent activation
of mast cells
Atopic disorders: hay fever, eczema, hives, asthma, reaction to bee sting
Drug hypersensitivity: penicillin rash or anaphylaxis
Type II Antibody-dependent
reaction
Complement-dependent reactions
Lysis: ABO mismatch, Goodpasture's syndrome, hyperacute transplantation
rejection
Phagocytosis: warm (IgG) autoimmune hemolytic anemia, ABO and Rh
hemolytic disease of newborn
Complement-independent reactions
Antibody (IgG, IgE)-dependent cell-mediated cytotoxicity: natural killer
cell destruction of neoplastic and virus-infected cells; helminth destruction
by eosinophils
Antibodies directed against cell surface receptors: myasthenia gravis,
Graves' disease
Type III Deposition of antigen-
antibody complexes
Systemic lupus erythematosus (DNA-anti-DNA)
Rheumatoid arthritis (IgM-Fc receptor IgG)
Serum sickness (horse antithymocyte globulin-antibody)
Type IV Antibody-independent
T cell-mediated reactions
Delayed type: contact dermatitis (e.g., poison ivy), tuberculous granuloma
Cell-mediated cytotoxicity: killing of tumor cells and virus-infected cells

Type I (immediate) hypersensitivity
 Also called allergic reactions, or allergies
 Induced by environmental antigens
(allergens) that stimulate strong TH2
responses and IgE production in
genetically susceptible individuals
 IgE coats mast cells by binding to Fcε
receptors
 re-exposure to the allergen leads to cross-
linking of the IgE and FcεRI, activation of
mast cells, and release of mediators.
 Mediators are responsible for the
immediate vascular and smooth muscle
reactions and the late-phase reaction
(inflammation).
 Principal mediators are
 histamine,
 proteases and other granule contents
 prostaglandins and leukotrienes
 cytokines.
 The clinical manifestations may be
 local - rhinitis
 systemic -anaphylaxis.

Type I (immediate)
hypersensitivity
 Allergen exposure
 IMMEDIATE phase: MAST cell DEgranulation,
vasodilatation, vascular leakage, smooth
muscle spasm
 LATE phase (hours, days): Eosinophils,
PMNs, T-Cells
 Clinical examples of type I
hypersensitivity
 Anaphylaxis,
 allergies,
 bronchial asthma (atopic forms)
 Tests used to evaluate type I
hypersensitivity
 Scratch test

Positive response is a histamine-mediated wheal-
and-flare reaction after introduction of an allergen
into the skin.
 Radioimmunosorbent test

Detects specific IgE antibodies in serum that are
against specific allergens

Type II (cytotoxic) hypersensitivity
 Antibody-dependent cytotoxic reactions
 Complement-dependent reactions

Lysis

Antibody (IgG or IgM) directed against antigen on the cell membrane activates
the complement system, leading to lysis by the membrane attack complex.
 Phagocytosis

Fixed macrophages (e.g., in spleen) phagocytose hematopoietic cells (e.g.,
RBCs) coated by IgG antibodies and/or complement (C3b).
 Complement-independent reactions

Antibody (IgG, IgE)-dependent cell-mediated cytotoxicity

Leukocytes with receptors for IgG or IgE lyse but do not phagocytose cells
coated by antibodies.
 IgG autoantibodies directed against cell surface receptors
 Tests used to evaluate type II hypersensitivity
 Direct Coombs' test detects IgG and/or C3b attached to RBCs.
 Indirect Coombs' test detects antibodies in serum (e.g., anti-D).

Type II (cytotoxic) hypersensitivity
Effector mechanisms
 A, Opsonization of cells by
antibodies and complement
components, and ingestion of
opsonized cells by phagocytes.
 B, Inflammation induced by
antibody binding to Fc
receptors of leukocytes and by
complement breakdown
products.
 C, Antireceptor antibodies
disturb the normal function of
receptors.
 antibodies against the thyroid-
stimulating hormone (TSH)
receptor activate thyroid cells
in Graves disease
 acetylcholine (ACh) receptor
antibodies impair
neuromuscular transmission in
myasthenia gravis.

Antibody-Mediated Diseases
(Type II Hypersensitivity)
 Autoimmune Hemolytic Anemia, AHA
 Idiopathic Thrombocytopenic Purpura, ITP
 Goodpasture Syndrome
 Nephritis and Lung hemorrhage
 Rheumatic Fever
 Myasthenia Gravis
 Graves Disease
 Pernicious Anemia, PA

Type III (immunocomplex) hypersensitivity
 Activation of the complement system by circulating antigen-antibody
complexes
 First exposure to antigen
 Synthesis of antibodies
 Second exposure to antigen
 Deposition of antigen-antibody complexes
 Complement activation, producing C5a, which attracts neutrophils that
damage tissue
 Arthus reaction
 Localized immunocomplex reaction
 Example-farmer's lung from exposure to thermophilic actinomycetes, or
antigens, in air
 Test used to evaluate type III hypersensitivity
 Immunofluorescent staining of tissue biopsies

example-glomeruli in glomerulonephritis

Type III (immunocomplex)
hypersensitivity
 Antigen/Antibody “Complexes”
 Kidney (Glomerular Basement
Membrane)
 Blood Vessels
 Skin
 Joints
 Common Type III Diseases
 SLE (Lupus),
 Poly(Peri)arteritis Nodosa,
 Poststreptococcal Glomerulonephritis,
 Arthus reaction (hrs),
 Serum sickness (days)

Type IV hypersensitivity
 Antibody-independent T cell-mediated reactions (cellular
immunity)
 Delayed reaction hypersensitivity
 CD4 cells interact with macrophages (APCs with MHC class II
antigens), resulting in cytokine injury to tissue.
 Cell-mediated cytotoxicity
 CD8 T cells interact with altered MHC class I antigens on
neoplastic, virus-infected, or donor graft cells, causing cell lysis.
 Test used to evaluate type IV hypersensitivity
 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.
 Skin reaction to Candida
 Clinical examples of type IV hypersensitivity

 Mechanisms of T-cell-
mediated (type IV)
hypersensitivity
reactions.
 A, 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+ CTLs directly kill
tissue cells.

 Tuberculin Skin Reaction
 DIRECT ANTIGENCELL CONTACT
 GRANULOMA FORMATION
 CONTACT DERMATITIS

SUMMARY
 I Acute allergic reaction
 II Antibodies directed against cell
surfaces
 III Immune complexes
 IV Delayed Hypersensitivity (Tb skin test)

Autoimmune Diseases
 Autoimmune dysfunction is associated with a loss of self-tolerance,
resulting in immune reactions directed against host tissue.
 Tolerance (unresponsiveness) to self-antigens is a fundamental property of
the immune system

Central tolerance:
 immature lymphocytes that recognize self-antigens in the central (generative) lymphoid
organs are killed by apoptosis; I
 n the B-cell lineage, some of the self-reactive lymphocytes switch to new antigen
receptors that are not self-reactive.

Peripheral tolerance
 mature lymphocytes that recognize self-antigens in peripheral tissues become
functionally inactive (anergic), or are suppressed by regulatory T lymphocytes, or die by
apoptosis.
 The variables that lead to a failure of self-tolerance and the development
of autoimmunity include
 inheritance of susceptibility genes that may disrupt different tolerance
pathways,
 infections and tissue alterations that may expose self-antigens and activate
APCs and lymphocytes in the tissues.

Mechanisms of autoimmunity
 Release of normally sequestered antigens
(e.g., sperm)
 Sharing of antigens between host and
pathogen
 Defects in functions of helper or suppressor
T cells
 Persistence of autoreactive T and B cells
 Presence of specific autoantibodies

CLASSIC AUTOIMMUNE DISEASES
SYSTEMIC
 Systemic lupus erythematosus
 Rheumatoid arthritis
 Sjögren syndrome
 Systemic sclerosis (scleroderma)
 Mixed connective tissue disease

CLASSIC AUTOIMMUNE DISEASES
LOCAL
 Hashimoto thyroiditis
 Autoimmune hemolytic anemia
 Multiple sclerosis
 Autoimmune orchitis
 Goodpasture syndrome
 Autoimmune thrombocytopenia
 “Pernicious” anemia
 Insulin dependent diabetes mellitus
 Myasthenia gravis


Autoantibodies in Autoimmune Disease
Autoantibodies Disease
Test Sensitivity
(%)
Antiacetylcholine receptor Myasthenia gravis 90
Anti-basement membrane Goodpasture syndrome >90
Anticentromere CREST syndrome 30
Antiendomysial and antigliadin Celiac disease 95
Anti-insulin, Anti-islet cell Type 1 diabetes 50, 75
Anti-intrinsic factor Pernicious anemia 60
Anti-parietal cell 90
Antimicrosomal Hashimoto's thyroiditis 97
Antithyroglobulin 85
Antimitochondrial Primary biliary cirrhosis 90-100
Antimyeloperoxidase Microscopic polyangiitis 80 (p-ANCA)
Antiproteinase 3 Wegener's granulomatosis >90 (c-ANCA)
Antiribonucleoprotein Mixed connective tissue disease 100
Anti-TSH receptor Graves' disease 85

Systemic lupus erythematosus (SLE)
 A systemic autoimmune disease
caused by autoantibodies produced
against numerous self-antigens and
the formation of immune complexes.
 Anti-nuclear autoantibodies, and the
ones responsible for the formation of
circulating immune complexes, are
directed against nuclear antigens.
 Other autoantibodies react with
erythrocytes, platelets, and various
complexes of phospholipids with
proteins.
 The underlying cause of the
breakdown in self-tolerance in SLE is

 Clinical findings
 Hematologic - autoimmune hemolytic anemia, thrombocytopenia,
leukopenia
 Lymphatic - generalized painful lymphadenopathy, splenomegaly
 Musculoskeletal - small-joint inflammation (hands) with absence of joint
deformity
 Skin - malar butterfly rash
 Renal – 5 types, diffuse proliferative glomerulonephritis the most often
 Cardiovascular - fibrinous pericarditis with or without effusion, Libman-Sacks
endocarditis (sterile vegetations on mitral valve)
 Respiratory interstitial fibrosis of lungs, pleural effusion with friction rub
 Pregnancy-related

complete heart block in newborns

Recurrent spontaneous abortions
 Drug-induced lupus erythematosus

Associated drugs - Procainamide, hydralazine

 Etiology: Antibodies (ABs) directed against the
patient’s own DNA, HISTONES, NON-histone RNA,
and NUCLEOLUS
 Pathogenesis: Progressive DEPOSITION and
INFLAMMATION to immune deposits, in skin, joints,
kidneys, vessels, heart, CNS
 Morphology: “Butterfly” rash, skin deposits,
glomerolunephritis (NOT discoid)
 Clinical expression: Progressive renal and vascular
disease, POSITIVE A.N.A.

 Laboratory findings in SLE
 Antinuclear antibody (ANA) (almost all cases)

Anti-double-stranded DNA antibodies and anti-Sm antibodies
 Used to confirm the diagnosis of SLE -highly specific for the disease
 Antiphospholipid antibodies

Lupus anticoagulant and anticardiolipin antibodies
 Damage vessel endothelium, producing vessel thrombosis
 Increased incidence of strokes and recurrent spontaneous abortions
 Lupus erythematosus cell

Neutrophil containing phagocytosed altered DNA
 Not specific for SLE
 Decreased serum complement

Used up with activation of complement system
 Immunocomplexes at the dermal-epidermal junction in skin
biopsies

Immunofluorescent studies identify complexes in a band-like
distribution along the dermal-epidermal junction.

Rheumatoid Arthritis
 Asystemic, chronic inflammatory disease
affecting many tissues but principally
attacking the joints
 to produce a nonsuppurative proliferative
synovitis that frequently progresses to destroy
articular cartilage and underlying bone with
resulting disabling arthritis
 In extra-articular involvement (skin, heart,
blood vessels, muscles, and lungs)-RA may
resemble SLE or scleroderma
 Immunology
 genetic predisposition, infections
 T-cell reaction, TNF –central role
 Rheumatoid factor (RF or RhF)
-antibody against the Fc portion of Ig G⇒
immune complexes

 Symmetric arthritis, principally
affecting the small joints of the hands
(proximal interphalangeal and
metacarpophalangeal joints) and feet,
ankles, knees, wrists, elbows, and
shoulders.
 Morphology
 Pannus formation, destruction of
bone, cartilage, ankylosis

synovial cell hyperplasia and
proliferation;

dense perivascular inflammatory cell
infiltrates (frequently forming lymphoid
follicles) in the synovium composed of
CD4+ T cells, plasma cells, and
macrophages

increased vascularity due to
angiogenesis

neutrophils and aggregates of
organizing fibrin on the synovial
surface and in the joint space

increased osteoclast activity in the
underlying bone, leading to synovial
penetration and bone erosion
A pannus, formed by proliferating synovial-
lining cells admixed with inflammatory cells,
granulation tissue, and fibrous connective
tissue

 Morphology
 Rheumatoid subcutaneous nodules -
in about one-fourth of patients,
occurring along the extensor surface
of the forearm or other areas
subjected to mechanical pressure

rarely they can form in the lungs,
spleen, heart, aorta, and other
viscera.

firm, nontender, oval or rounded
masses as large as 2 cm in
diameter.

Microscopically, they are
characterized by a central focus of
fibrinoid necrosis surrounded by a
palisade of macrophages, which in
turn is rimmed by granulation tissue
 Pleuritis/pericarditis -fibrinous
 Lung - interstitial fibrosis.
 Ocular changes –uveitis,
keratoconjunctivitis

Systemic Sclerosis
(Scleroderma)
 Excessive production of
collagen that primarily
targets the skin, GIT, lungs,
and kidneys
 Occurs predominantly in
women of childbearing age
 Pathogenesis
 Small-vessel endothelial cell
damage produces blood vessel
fibrosis and ischemic injury.
 T-cell release of cytokines
results in excessive collagen
synthesis.
clawlike appearance , ulcerations
increase of compact collagen in the dermis
along with thinning of the epidermis, atrophy of
the dermal appendages, and hyaline thickening
of the walls of dermal arterioles and capillaries

Systemic Sclerosis
(Scleroderma)
 Two groups based on its clinical course
 Diffuse scleroderma, characterized by initial widespread skin
involvement, with rapid progression and early visceral involvement
 Limited scleroderma (CREST syndrome) - with relatively mild skin
involvement, often confined to the fingers and face and
involvement of the viscera occurs late

C-calcification, centromere antibody

R-Raynaud's phenomenon

E-Esophageal dysmotility

S-sclerodactyly (i.e., tapered, claw-like fingers)

T-telangiectasis (i.e., multiple punctate blood vessel dilations)
 Laboratory findings in systemic sclerosis
 Serum ANA is positive in 70% to 90% of cases.

Antitopoisomerase antibody –in diffuse sclerosis

Anticentromere antibodies in 30% of cases

Systemic Sclerosis
(Scleroderma)
 Clinical findings/Morphology
 Raynaud's phenomenon

Sequential color changes caused by digital vessel vasculitis and fibrosis, digital infarcts

heart (cardiac Raynaud) - microvascular injury and resultant ischemia
 Skin

Skin atrophy and tissue swelling beginning in the fingers and extending
proximally

Extensive dystrophic calcification in subcutaneous tissue

Tightened facial features (radial furrowing around the lips)
 Gastrointestinal

Dysphagia for solids and liquids

Malabsorption

Diverticula (bacterial overgrowth)

Progressive atrophy and collagenous fibrous replacement of the muscularis
at any level of the gut
 Respiratory

Interstitial fibrosis of lungs, respiratory failure
 Renal

Vasculitis involving interlobular arteries and glomeruli, hypertension

Dermatomyositis /polymyositis
 Immune-mediated muscle injury and inflammation
 Occurs predominantly in women 40 to 60 years of age
 Associated with risk of malignant neoplasms (15-20% of
cases), particularly lung cancer, stomach
 Pathogenesis
 DM is associated with antibody-mediated damage.
 PM is associated with T cell-mediated damage.
 Muscle pain and atrophy

large muscles of the trunk, neck, and limbs

Shoulders are commonly involved.
 Heliotrope eyelids or "raccoon eyes" (purple-red eyelid
discoloration)
 Laboratory findings
 Serum ANA is positive in fewer than 30% of cases

Jo-1 antibodies, directed against transfer RNA synthetase .
 Increased serum creatine kinase
 Muscle biopsy shows a lymphocytic infiltrate.

Polyarteritis Nodosa
 A systemic vasculitis of small or medium-sized muscular
arteries, typically involving renal and visceral vessels but
sparing the pulmonary circulation
 segmental transmural necrotizing inflammation (part of the
vessel circumference)

acute phase there is transmural inflammation of the arterial wall
with a mixed infiltrate of neutrophils, eosinophils, and
mononuclear cells, frequently accompanied by fibrinoid
necrosis

The inflammatory process weakens the arterial wall and can
lead to aneurysms or even rupture
 The most common manifestations are:
 malaise, fever, and weight loss
 hypertension, usually developing rapidly
 abdominal pain and melena (bloody stool) caused by
vascular GI lesions
 diffuse muscular aches and pains
 peripheral neuritis, predominantly affecting motor nerves
 Renal (arterial) involvement –a common and a major cause
of death
 Biopsy is necessary to confirm the diagnosis


Mixed connective tissue disease
(MCTD)
 Signs and symptoms similar to SLE,
systemic sclerosis, and PM
 distinct disease or represents heterogeneous
subsets of SLE, systemic sclerosis, and PM
 Renal disease is uncommon.
 Immunology
 Antiribonucleoprotein antibodies are positive in
almost 100% of cases.

Sjögren Syndrome
 An inflammatory disease that affects primarily the
salivary and lacrimal glands, causing dryness of
the mouth (xerostomia) and eyes
(keratoconjunctivitis)
 other secretory glands (nasopharynx, upper airway,
vagina) may also be involved
 extraglandular disease affecting the CNS, skin,
kidneys, and muscles
 increased risk for non-Hodgkin B-cell lymphoma
(marginal-zonal type)
 The disease is believed to be caused by an
autoimmune T-cell reaction against an unknown
self antigen(s) expressed in these glands, or
immune reactions against the antigens of a virus
that infects the tissues
 autoantibodies to the ribonucleoprotein antigens
SS-A (Ro) and SS-B (La)
 Morphology

response. Immunologic
deficiency syndromes.
Transplantation immunity.

Immunodeficiency Disorders
 Defects in B cells, T cells,
complement, or phagocytic cells
 primary (genetic)
 secondary (acquired)

Congenital immunodeficiency
disorders
 B-cell disorders
 Recurrent encapsulated bacterial
infections (e.g., Streptococcus
pneumoniae)
 T-cell disorders
 Recurrent infections caused by
intracellular pathogens (fungi, viruses,
protozoa)
 Combined B- and T-cell disorders

Examples of Infections in Immunodeficiencies
Pathogen
Type T-Cell-Defect B-Cell Defect
Granulocyte
Defect
Complement
Defect
Bacteria Bacterial sepsis Streptococci,
staphylococci,
Haemophilus
Staphylococci,
Pseudomonas
Neisserial
infections, other
pyogenic
bacterial
infections
Viruses Cytomegalovirus, Epstein-
Barr virus, severe
varicella, chronic
infections with respiratory
and intestinal viruses
Enteroviral
encephalitis
Fungi and
parasites
Candida, Pneumocystis
carinii
Severe intestinal
giardiasis
Candida,
Nocardia,
Aspergillus
Special
features
Aggressive disease with
opportunistic pathogens,
failure to clear infections
Recurrent
sinopulmonary
infections, sepsis,
chronic
meningitis

PRIMARY
 CHILDREN with repeated, often severe infections, cellular
AND/OR humoral immunity problems, autoimmune defects
 BRUTON (X-linked agammaglobulinemia)
 Common variable immunodeficiency
 IgA deficiency
 Hyper IgM
 DI GEORGE (THYMIC HYPOPLASIA) 22q11.2
 SCID (Severe Combined Immuno Deficiency)
 WISKOTT-ALDRICH
 thrombocytopenia and eczema
 Complement deficiencies

ADA=
ADENOSINE
DEAMINASE
 Bruton’s x-linked
agammaglobulemia
 NO tyrosine kinase (BTK gene)
 Common variable immunodeficiency
 Various genetic defects, both
B and T cells
 IgA deficiency
 Unknown
 Hyper IgM
 CD40-L gene defect
 DiGeorge:
 22q11 deletion
 failure of development of 3rd
and
4th
pharyngeal pouch.
 SCID
 Early T-Cell failure
Primary Immunodeficiency Disorders

Disease Defect(s) Clinical Features
B-Cell Disorders
Bruton's
agammaglobulinemia
Failure of pre-B cells to become mature
B cells
Mutated tyrosine kinase
X-linked recessive disorder
Sinopulmonary infections
Maternal antibodies protective from birth to age 6 months
↓ Immunoglobulins
IgA deficiency Failure of IgA B cells to mature into
plasma cells
Sinopulmonary infections, giardiasis
Anaphylaxis if exposed to blood products that contain IgA
↓ IgA and secretory IgA
Common variable
immunodeficiency
Defect in B-cell maturation to plasma
cells
Adult immunodeficiency disorder
Sinopulmonary infections, GI infections (e.g., Giardia), pneumonia,
autoimmune disease
↓ Immunoglobulins
T-Cell Disorder
DiGeorge syndrome Failure of third and fourth pharyngeal
pouches to develop
Thymus and parathyroids fail to develop
Hypoparathyroidism (tetany); absent thymic shadow on radiograph;
PCP
Danger of GVH reaction
Combined B- and T-Cell Disorders
Severe combined
immunodeficiency (SCID)
deaminase deficiency; adenine toxic to
B and T cells, ↓ deoxynucleoside
triphosphate precursors for DNA
synthesis
Autosomal recessive disorder
Defective CMI
↓ Immunoglobulins
Treatment: gene therapy, bone marrow transplant (patients with
SCID do not reject allografts)
Wiskott-Aldrich syndrome Progressive deletion of B and T cells
X-linked recessive disorder
Symptom triad: eczema, thrombocytopenia, sinopulmonary infections
Associated risk of malignant lymphoma
Defective CMI
↓ IgM, normal IgG, ↑ IgA and IgE
Ataxia-telangiectasia Mutation in DNA repair enzymes
Thymic hypoplasia
Autosomal recessive disorder
Cerebellar ataxia, telangiectasias of eyes and skin
Risk of lymphoma and/or leukemia
↑ Serum α-fetoprotein

Secondary
 Autoimmune diseases (e.g., systemic lupus
erythematosus)
 Lymphoproliferative disorders (e.g., malignant
lymphoma)
 Infections (e.g., human immunodeficiency virus,
HIV)
 Immunosuppressive drugs (e.g., corticosteroids)
 Radiotherapy

AIDS
Acquired immunodeficiency syndrome
 Etiology: HIV
 Pathogenesis: Infection,
Latency, Progressive T-Cell loss
 Morphology:
 Clinical Expressions: Infections,
Neoplasms, Progressive Immune Failure,
Death, HIV+, HIV-RNA (Viral Load)

EPIDEMIOLOGY
 HOMOSEXUAL (40%, and declining)
 INTRAVENOUS DRUG USAGE (25%)
 HETEROSEXUAL SEX (10% and rising)
 OTHER MODES OF TRANSMISSION
 Vertical transmission - transplacental route, blood contamination during
delivery, breast-feeding
 Accidental needlestick

Most common mode of infection in health care workers
 Blood products

Risk per unit of blood is 1 per 2 million units of blood transfused.
 Body fluids containing HIV
 Blood, semen, breast milk
 Virus cannot enter intact skin or mucosa

AIDS
 Etiology
 RNA retrovirus

HIV-1 is the most common cause in the USA

HIV-2 is the most common cause in developing countries.
 Pathogenesis
 HIV envelope protein (gp120) attaches to the CD4 molecule of T
cells.
 HIV infects CD4 T cells, causing direct cytotoxicity.
 Infection of non-T cells

Can infect monocytes and macrophages in tissue (e.g., lung, brain)

Can infect dendritic cells in mucosal tissue

Dendritic cells transfer virus to B-cell germinal follicles.
 Macrophages and dendritic cells are reservoirs for virus.

Loss of cell-mediated immunity
 Reverse transcriptase

Converts viral RNA into proviral double-stranded DNA

DNA is integrated into the host DNA.

AIDS
 Acute phase
 Mononucleosis-like syndrome 3 to 6 weeks after infection
 Latent (chronic) phase
 Asymptomatic period 2 to 10 years after infection
 CD4 T-cell count greater than 500 cells/μL
 Viral replication occurs in dendritic cells (reservoir cells) in germinal follicles of LN
 Early symptomatic phase
 CD4 T-cell count 200 to 500 cells/μL
 Generalized lymphadenopathy
 Non-AIDS-defining infections - EBV-caused glossitis, oral candidiasis
 Fever, weight loss, diarrhea
 AIDS
 Criteria

HIV-positive with CD4 T-cell count of 200 cells/μL or less or an AIDS-defining condition
 Most common AIDS-defining infections

Pneumocystis jiroveci pneumonia, systemic candidiasis
 AIDS-defining malignancies

Kaposi's sarcoma, Burkitt's lymphoma (EBV), primary CNS lymphoma (EBV)
 Causes of death

Disseminated infections (cytomegalovirus, Mycobacterium avium complex)

AIDS
1) PRIMARY INFECTION
2) LYMPHOID INFECTION
3) ACUTE SYNDROME
4) IMMUNE RESPONSE
5) LATENCY
6) AIDS

INFECTIONS of AIDS
 Protozoal/Helminthic
 Cryptosporidium, Pneumocystis Carinii
Pneumonia, Toxoplasmosis
 Fungal
 Candida
 Bacterial
 TB, Nocardia, Salmonella
 Viral
 CMV, HSV, VZ

CANCERS of AIDS
 KAPOSI SARCOMA
 B-CELL LYMPHOMAS
 CNS LYMPHOMAS
 CERVIX CANCER, SQUAMOUS
CELL

AIDS
 Immunologic abnormalities
 Lymphopenia (low CD4 T-cell count)
 Cutaneous anergy (defect in cell-mediated immunity)
 Hypergammaglobulinemia (due to polyclonal B-cell stimulation by EBV)
 CD4:CD8 ratio <1
 CD4 count and risk for certain diseases
 700 to 1500: normal
 200 to 500: oral thrush, herpes zoster (shingles), hairy leukoplakia
 100 to 200: Pneumocystis jiroveci pneumonia, dementia
 Below 100: toxoplasmosis, cryptococcosis, cryptosporidiosis
 Below 50: CMV retinitis, Mycobacterium avium complex, progressive
multifocal leukoencephalopathy, primary central nervous system
lymphoma
 Pregnant women with AIDS
 Treatment with a reverse transcriptase inhibitor reduces transmission to
newborns to less than 8%.

Types of grafts
 Autograft (i.e., self to self)
 Associated with the best survival rate
 Syngeneic graft (isograft)
 Between identical twins
 Allograft
 Between genetically different individuals of the
same species
 Xenograft
 Between two species
 Example-transplant of heart valve from pig to
human

Types of transplants
 Cornea
 Best allograft survival rate
 Danger of transmission of Creutzfeldt-Jakob
disease
 Kidney
 Better survival with kidney from living donor than
from cadaver
 Bone marrow
 Graft contains pluripotential cells that repopulate
host stem cells
 Host assumes donor ABO group
 Danger of graft-versus-host reaction and
cytomegalovirus infection

Transplantation Immunology
 Transplantation rejection involves a
humoral or cell-mediated host response
against MHC antigens in the donor
graft.
 There are two main mechanisms by
which the host immune system
recognizes and responds to the MHC
molecules on the graft
 Direct recognition

donor class I and class II MHC antigens
on APCs in the graft are recognized by
host CD8+ cytotoxic T cells and CD4+
helper T cells, respectively.

CD4+ cells proliferate and produce
cytokines (e.g., IFN-γ), which induce
tissue damage by a local delayed-
hypersensitivity reaction.

CD8+ T cells responding to graft
antigens differentiate into CTLs that kill
graft cells.
 Indirect recognition

graft antigens are displayed by host
APCs and activate CD4+ T cells, which
damage the graft by a local delayed-
hypersensitivity reaction and stimulate B
lymphocytes to produce antibodies.
Direct pathway Indirect pathway

Types of rejection
 On the basis of the mechanisms involved, the
resulting morphology, and the tempo of the
various processes, rejection reactions have
been classified as:
 Hyperacute (minutes)

AG/AB reaction of vascular endothelium

Acute (days months)

cellular (INTERSTITIAL infiltrate) and humoral
(VASCULITIS)
 Chronic (months)

slow vascular fibrosis

Types of rejection
 Hyperacute rejection
 Irreversible reaction occurs
within minutes.
 Pathogenesis

ABO incompatibility or action of
preformed anti-HLA antibodies in
the recipient directed against
donor antigens in vascular
endothelium

Type II hypersensitivity reaction
 Pathologic finding

Vessel thrombosis
 Example-blood group A person
receives a blood group B heart.

Types of rejection
 Acute rejection
 Most common transplant rejection
 Reversible reaction that occurs within
days to weeks

Type IV cell-mediated hypersensitivity
 CD4 T cells release cytokines,
resulting in activation of host
macrophages, proliferation of CD8 T
cells, and destruction of donor graft
cells.
 Extensive interstitial round cell
lymphocytic infiltrate in the graft,
edema, and endothelial cell injury

Antibody-mediated type II
hypersensitivity reaction
 Cytokines from CD4 T cells promote
B-cell differentiation into plasma cells,
producing anti-HLA antibodies that
attack vessels in the donor graft.
 Vasculitis with intravascular
thrombosis in recent grafts
 Intimal thickening with obliteration of
vessel lumens in older grafts

Types of rejection
 Chronic rejection
 Irreversible reaction
that occurs over
months to years
 Pathogenesis

probably caused by
T-cell reaction and
secretion of
cytokines that induce
proliferation of
vascular smooth
muscle cells,
associated with
parenchymal fibrosis.
 Blood vessel damage
with intimal thickening
and fibrosis

Factors enhancing graft viability
 ABO blood group compatibility between
recipients and donors
 Absence of preformed anti-HLA cytotoxic
antibodies in recipients
 People must have previous exposure to blood
products to develop anti-HLA cytotoxic antibodies.
 Close matches of HLA-A, -B, and -D loci between
recipients and donors

Transplantation of Hematopoietic Cells
Graft-versus-host (GVH) reaction
 Causes
 Potential complication in bone marrow and liver
transplants
 Potential complication in blood transfusions given to
patients with a T-cell immunodeficiency and newborns.
 Pathogenesis
 Donor T cells recognize host tissue as foreign and
activate host CD4 and CD8 T cells.
 Bile duct necrosis (jaundice)
 Gastrointestinal mucosa ulceration (bloody diarrhea)
 Dermatitis

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