PATHOLOGY
Immunopathology 2
Dr. Joselli c. Rueda-Cu
I. Autoimmune Diseases
II. Immunodeficiency Syndromes
a. Primary Immunodeficiency
b. AIDS
AUTOIMMUNE DISEASES
Self tolerance- lack of responsiveness to an individuals own
antigen
Autoimmune disease Lack of Self tolerance
May be influenced by 2 factors:
a. Inheritance MHC genes
b. Infections
May be organ specific or systemic
"Connective tissue" disorders because many are manifested
in a variety of tissues
Hypersensitivity reactions involved in autoimmunity:
o Type II (Antibody-mediated)
o Type III (Immune complex- mediated)
o Sometimes Type IV (Cell-mediated)
Mechanisms proposed for development of autoimmunity
Bypass of CD4+ T-cell tolerance of "self" antigens
Complex of antigen with a hapten (Such as a drug or
infectious agent) or infectious degradation of an antigen
Molecular Mimicry
o Cross-reaction with a hapten on an infectious agent that is
similar to tissue proteins
o Classic for post-streptoccocal glomerulonephritis and
rheumatic heart disease
o Streptococcus shares a similarity with the mast cell of the
heart and kidney, the reason why they are affected
The immune system will produce Ab that is suppose
to destroy the organism but due to the similarity
attacks the organs instead
Direct activation of B-cell (leading to autoantibody production)
via bacterial endotoxin and via Epstein-Barr virus
receptors on B-cells
Idiotype bypass through Ligand Mimicry, as seen in anti-
receptor antibody mediated disease, and cross-reactivity with
infectious agents:
o T-suppressor/helper imbalance
o Emergence of a sequestered antigen through tissue
trauma or inflammatory destruction.
Examples include: Lens crystalline of eye,
spermatozoa in testis, and myelin in CNS
Note:
Tissue damage Release of self antigens that are sequestered
(meaning, hidden) Exposes epitopes that are normally
concealed Lymphocyte activation.
Antinuclear Antibodies (ANA)
Seen in many autoimmune diseases but not diagnostic
because may suggest many diseases as well
In general, the higher the titer, the worse the disease.
The titer is simply the highest dilution of patient serum at
which the test is still positive
Refer to table 6-9 p. 215 of Robbins
Note:
Nucleus Part of cell that is antigenic
(+) ANA indication that patient has autoimmune disease
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July 26- 28, 2011
Characteristic fluorescent staining patterns for ANA: (must
memorize!)
1. Homogenous (Diffuse) Not very specific for anything
2. Rim May be indicative of anti-double stranded DNA,
seen in Systemic Lupus Erythematosus (SLE)
Note:
Crithidia org Serves as substrate for the double stranded
DNA test. A positive result strongly suggests SLE
3. Speckled Indicative of antibody to extractable nuclear
antigens, often seen in Mixed Connective Tissue Disease
(MCTD)
4. Nucleolar Antibody to nucleolar RNA, seen often in
PSS (Progressive Systemic Sclerosis, Scleroderma)
5. Centromere Antibody to centromeric protein, seen in
CREST syndrome (Limited Scleroderma)
Note:
Refer to page 3 under Patterns of Diseases of PSS for
meaning of CREST
Though no autoantibody is completely sensitive or specific
for a particular autoimmune disease, some of the strongest
associations include:
(Must memorize)
1. Anti-double stranded DNA (native DNA antibody): SLE
2. Anti-Smith: SLE
3. Anti-histone: Drug-induced SLE
4. Anti SS-A and anti SS-B: Sjogren's syndrome
5. Anti DNA-topoisomerase I (Scl-70): PSS
6. Anti-histidyl-tRNA synthetase (Jo-1): Polymyositis
7. Anti-RNP (Ribonucleoprotein): MCTD
8. Anti-phospholipid antibody (Anti-cardiolipin antibody):
SLE and others
ANA test used for screening of autoimmune diseases. P
o Patient serum is incubated with a tissue substrate to which
any auto-antibodies to nuclear antigens will bind.
o Then, a fluorosceinated antibody is added and the tissue
is observed under fluorescence microscopy to see if
staining is present
Fig. 1. Homogenous" pattern of nuclear staining of a positive ANA. This means, the
entire nuclear substance is antigenic to antibody
Pathology 1 | 9
 Systematic Lupus Erythematosus (SLE)
Expression of ANA w/c are against DNA, histones, non-
histone proteins of RNA and Nucleolar antigens
Mechanism is Type III hypersensitivity (DNA-antiDNA
complexes)
Suggestive serologic and clinical findings:
1. Skin rash
Malar or discoid (Butterfly rash)
Fig. 2. This is the so-called "rim" pattern that is more characteristic of systemic
To differentiate malar rash of SLE and DLE: Biopsy
lupus erythematosus (SLE) than other autoimmune diseases. affected and unaffected areas. SLE if pathology on
both. DLE if only in affected area.
2. Sensitivity to light (Photodermatitis)
3. Serositis
Inflammation of serosal surfaces along with effusions
4. Glomerulonephritis
The worst problem with SLE
Immune complexes accumulate in glomeruli
5. Cytopenias
Anemia, leukopenia, thrombocytopenia due to ANA
specific for RBC, WBC and platelets
6. Antinuclear antibody
Fig. 3. Here the little critters have brightly fluorescing kinetoplasts indicative of a Rim pattern, anti double stranded-DNA, anti-Smith
positive test. A positive double stranded DNA test strongly suggests a diagnosis of
SLE.
autoantibodies (Most specific for SLE)
7. Arthralgias, myalgias
8. Vasculitis
CNS, skin, kidney, etc
9. Decreased serum complement
Especially C1q
10. Thrombosis (Arteries or veins)
11. Genetic factors
Tends to run in families
Association with HLA Dr-2 and Dr-3
More common in young women (especially African-
American)
Fig. 4. This is the so-called "speckled" pattern of antinuclear antibody test staining
which is more characteristic of the presence of autoantibodies to extractable nuclear Drugs can produce "drug-induced" SLE: Procainamide,
antigens (ENA), particularly to ribonucleoprotein. This pattern is not very specific, hydralazine, isoniazid, d-penicillamine.
but may be seen with an entity called "mixed connective tissue disease" (MCTD)
which is an "overlap" condition that is a mix among SLE, scleroderma, and Note:
polymyositis features.
Pathology of SLE in skin In dermoepidermal junction
undergoes vacuolization and dissolution due to C3 and Ig in the
junction.

Fig. 5. This is the so-called "nucleolar pattern" of staining in which the bright
fluorescence is seen within the nucleoli of the Hep2 cells. This pattern is more
suggestive of progressive systemic sclerosis (scleroderma).

Fig 7. Histologically, the skin of a patient with SLE may demonstrate a vasculitis
and dermal chronic inflammatory infiltrates, as seen here. Vasculitis with
autoimmune disease (Often related to deposition of antigen-antibody
complexes) can occur in many different organs and can lead to the often confusing
signs and symptoms of patients with rheumatic diseases.

Fig. 6. Here is the famous "LE cell" test which has value only in demonstrating how
the concept of autoantibodies works. The pink blobs are denatured nuclei. Here are
two, with one seen being phagocytosed in the center by a PMN. This test is not
nearly as sensitive as the ANA which has supplanted the LE cell test. Therefore,
NEVER order an LE cell test.

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 Scleroderma (Progressive Systemic Sclerosis)
Excessive fibrosis in various tissues from collagen deposition
by activated fibroblasts.
About 75% of cases are women, mostly middle-aged.
ANA, especially Scl-70 are very specific
Patient presents with the taut and shiny skin
The skin becomes inelastic and it is hard to move the fingers.
If sclerodactyly is seen along with calcinosis, Raynaud
phenomenon, esophageal dysmotility, and telangietasias,
then the best diagnosis is CREST syndrome ("limited"
scleroderma).
Fig. 8. Here is a more severe inflammatory skin infiltrate in the upper dermis of a
patient with SLE in which the basal layer of epidermis is undergoing vacuolization
Patterns of Diseases of PSS
and dissolution, and there is purpura with RBCs extravasated into the upper 1. Limited scleroderma, or CREST syndrome
dermis (which are the reasons for the rash). The benign form of PSS, visceral involvement occurs
Note: late, serologically suggested by the presence of anti-
If immunofluorescence microscopy using an antibody to centromere antibody
complement or immunoglobulin is performed, then one can see C = Calcinosis in skin and elsewhere
the brightly fluorescing band along the dermal epidermal junction R = Raynaud's phenomenon, sensitivity to cold
that indicates immune complex deposits are present. A variety of Serious consequence: the fingertips are
immunoglobulins can be present, usually IgG, and the immune blackened and additional portions of the hand
complexes trigger the "classic" complement cascade so that purplish with early gangrenous necrosis from
components such as C3 are present. If such a pattern is seen vasospasm with the Raynaud phenomenon.
only in skin involved by a rash, then the pattern is more E = Esophageal dysmotility from submucosal
characteristic for DLE, but if this pattern appears even in skin fibrosis
uninvolved by a rash, then SLE may underlie this S = Sclerodactyly from dermal fibrosis
phenomenon. Taut and shiny skin which becomes inelastic
The periarteriolar fibrosis ("onion skinning") seen in the and it is hard to move the telangietasias fingers
spleen in patients with SLE at autopsy is quite striking, though of T = Telangiectasias
no major clinical consequence. This results from vasculitis. Note:
Patient comes with difficulty of swallowing, shiny, mask-like
face, rigidity of hands. Suspect CREST syndrome.
2. Diffuse scleroderma: Worst form, visceral involvement
(kidney, lungs) occurs early
Scl-70 (anti-DNA topoisomerase I) antibody specific for
this form.
findings:
+ CREST
Renal arterial intimal thickening and proliferation
(Hyperplastic arteriolosclerosis) leading to
malignant hypertension with arterial fibrinoid
necrosis, thrombosis, and renal infarction.
Fig. 9. One of the feared complications of the autoimmune diseases is renal failure.
Half of patients die from renal disease
This is most likely to occur with SLE and the diffuse form of scleroderma. The Lungs : Diffuse alveolar fibrosis leading to
glomerulus has capillary loops that are markedly pink and thickened such that honeycomb fibrosis Pulmonary hypertension
capillary lumens are hard to see. This is characteristic for lupus nephritis. Morphea: Skin fibrosis
Discoid Lupus Erythematosus (DLE) Note:
A benign disease with skin involvement (MALAR rash/ SLE and Diffuse scleroderma are autoimmune diseases
Butterfly rash); showing renal involvement.
Not involve other part of the body
Skin manifestations mimic that of SLE
ANA positive in only a third (1/3)
Some progress to SLE (< 5% of patients)
Difference between malar rash and discoid:
o Reaction to anti-Smith
o Discoid: (+) ANA , (-) DNA

Mixed Connective Tissue Disease (MCTD)

A wastebasket category for patients who do not clearly fit into
other categories.
There are features similar to SLE, scleroderma, and
polymyositis. Fig. 10. At low magnification, there is a greater amount and depth of dermal
Most patients are middle aged females. collagen, leading to the decrease in elasticity. Though scleroderma (systemic
Characteristic feature is a speckled ANA pattern, anti-RNP sclerosis) is an autoimmune disease, the main microscopic feature is fibrosis, and
chronic inflammatory cell infiltrates are sparse, unlike SLE.
specific

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Fig. 11. This trichrome stain of the stomach demonstrates intense blue staining in
the submucosa from the collagen deposition. Such fibrosis can occur anywhere in
the gastrointestinal tract, but is most common in the lower esophagus, leading to the
esophageal dysmotility that is characteristic for systemic sclerosis.
Polymyositis-Dermatomyositis
Symmetrical inflammation of skeletal muscle with weakness
Sometimes associated with skin rash
o Dermatomyositis: Vasculitis in muscle and skin due to
Ag-Ab complex deposition
Multiple muscle involvement
Associated Ab is against nuclear antigen PMI and JO-Is are
very specific
Heliotropic rash: Purplish red tint on upper eyelids
pathognomonic (Looks like eyelids with purple eyeshadow)
Seen mostly in women in ages 40-60, also in ages 5-15
Inflammation mainly mediated by cytotoxic CD8 cells
Some adults (10-20%) develop cancer
Siogrens Syndrome
Dry eyes, dry mouth: Lacrimal and salivary gland
involvement by lymphocytic infiltration, fibrosis, and
destruction mediated by CD4+ cells helping antibody
production (Anti-SS-A and anti-SS-B are the most specific)
Infiltrate contains primarily CD4+ T cells
Enlargement of salivary glands
Involves type II and IV hypersensitivity
At high risk for development of B cell lymphoma
Most patients are middle to older-aged women
Mikulicz's syndrome:
o Lacrimal and salivary gland inflammation and dryness
o Encompassing
o Only a part of Sjogren's syndrome
IMMUNODEFICIENCY DISORDERS
Primary Immunodeficiency Disorders
Almost always genetically determined
Unlike secondary IDs which arise as complications of
infections, malnutrition, aging, side effects of
immunosuppression, irradiation or chemotherapy for cancer
and other autoimmune diseases
T cell defects almost always lead to impaired Ab synthesis
thus deficiencies in T cells are often indistinguishable from
combined deficiencies of T and B cells
Most primary immunodeficiencies manifest themselves in
infancy (detected since infants are very susceptible to
infections)
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X-Linked Agammaglobulinemia of Bruton
B lymphocytes affected
Genetic (Congenital agammaglobulinemia)
Failure of B-cell precursors to mature into B cells
Normal maturation of B cells in the bone marrow:
o Ig heavy-chain genes are rearranged first, followed by
rearrangement of the light chain genes
In the case of agammaglobulinemia:
o B cell maturation stops after the rearrangement of heavy
chain genes and light chains are not produced
o Thus complete Ig is not assembled
The mutations affect production of a tyrosine kinase (Bruton
tyrosine kinase, or btk) active in early pre-B cells which
diminishes their maturation and leads to virtual absence of all
immunoglobulin classes
Genetic defect on the long arm of X chromosome
(Xq.21.22)
Males primarily affected (inheritance occurs in an X-lined
recessive pattern) while females are carriers
Sporadic cases seen in females
Disease usually does not become apparent until about 6
months of age, when maternal Igs are depleted (genetic)
Infants are observed to have multiple infections with bacterial
organisms (Hemophilus, Staphylococcus, Streptococcus
pneumoniae), particularly in skin and lung
Agammaglobulinemia is the result of absent B-cells, but T-cell
mediated immunity is intact
o Thus most viral, fungal, and protozoal infections are
handled normally
If affected persons survive, many will develop autoimmune
diseases (arthritis and dermatomyositis)
The classic form of this disease has the following
characteristics:
a. B cells are absent or markedly decreased in the
circulation
b. Serum levels of all classes of Ig are depressed
c. Germinal centers of lymph nodes, Peyer patches, the
appendix, and tonsils are underdeveloped or
rudimentary
d. Plasma cells are absent throughout the body
e. T cell-mediated reactions are entirely normal
Treatment: Replacement therapy with Igs
Prophylactic IV Ig therapy allows most individuals to reach
adulthood
Not a humoral immune response
Common Variable Immunodeficiency
Heterogenous group of disorders
Common feature to all patients:
o Hypogammaglobulinemia Generally affecting all the
antibody classes but sometimes only IgG.
Incidence: 1 per 100,000
Involve both humoral and cell mediated immunity.
Normal numbers of circulating B lymphocytes, with impaired
secretion of one or more immunoglobulin isotypes, usually
IgG or IgA.
Clinical manifestations are caused by immunodeficiency and
hence they resemble those of X-linked agammaglobulinemia
Affects both female and male (Difference from X-liked
Agammaglobulinemia of Bruton)
Onset of symptoms: Childhood or adolescence
Normal numbers of circulating B lymphocytes, with
impaired secretion of one or more immunoglobulin isotypes,
usually IgG or IgA.
Lymphoid follicles are hyperplastic meaning B cells proliferate
in response to antigen but do not produce antibodies
Pathology 4 | 9
 Selective abnormality of T cell activation, as demonstrated by
decreased synthesis of interleukins (IL 2, 4, and 5)
Patients may have impaired gastrointestinal mucosal
immunity.
Variants
a. Either a decrease in CD4 cells or an increase in CD8
cells.
b. Presence of T and B lymphocyte autoantibodies.
At least two of the three main serum immunoglobulin isotypes
are decreased.
Persons are prone to recurrent bacterial infections,
particularly sinusitis, bronchitis, pneumonia, bronchiectasis,
and otitis.
Bordatella pertussis infections occur in childhood.
Viral infections are uncommon, though recurrent herpes
simplex with eventual herpes zoster is an exception.
Giardiasis is common.
Hypoplastic germinal centers and other B cell areas, no
plasma cells
Half are diagnosed before age 21, in some, complications do
not develop until adolescence or adulthood.
Increased incidence of autoimmune diseases:
o Hemolytic anemia
o Thrombocytopenia
o Pernicious anemia
In about two thirds of cases, normal numbers of circulating B
lymphocytes are present
Decrease in immunoglobulins, generally in all classes, more
often IgG and IgA, sometimes only of IgG.
DiGeorge Syndrome
Field defect of third and fourth pharyngeal pouch (which
develops to thymus and parathyroids) development in
utero during organogenesis in the first trimester of pregnancy
As a consequence, there is a variable loss of T-cell mediated
immunity (due to loss of thymus), tetany (lack of parathyroids)
and congenital defects of the heart and great vessels
Appearance of the mouth, ears and facies may be abnormal
A specific deletion on the long arm of chromosome 22
(22q11 thus not a familial disorder)
Anatomic structures that may be aplastic or hypoplastic
a. Thymus
b. Parathyroid
c. Great vessels
d. Esophagus
Sub classification:
a. Complete: Almost total absence of thymic tissue
b. Partial: Only a decrease in thymic tissue
Complete DiGeorge syndrome
o Normal levels of circulating immunoglobulin, though in
some cases serum IgE is increased and IgA decreased
o Markedly decreased numbers of circulating T
lymphocytes: Susceptible to fungal and viral infections
Children with partial DiGeorge syndrome
o Slight decrease in peripheral lymphocytes
o Extremely small but histologically normal thymus
o T cell function improves with age
o Increased infections, but with less frequency and with less
severity than children with the complete form.
o Accompanying aplasia of parathyroid glands: life-
threatening hypocalcemia that may appear soon after
birth.
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Severe Combined Immunodeficiency
Failure in development of both humoral and cell-mediated
immunity
Infants present with prominent thrush, extensive diaper rash,
failure to thrive
Without bone marrow transplantation, death occurs within the
first year of life
The major variants of SCID include:
A. X-linked form:
Mutation on the long arm of the X chromosome
Defective gamma chain of the interleukin-2
receptor (cytokine receptor) Renders early
lymphocytes incapable of normal differentiation and
development to functional T and B cells in response
to growth factors
Accounts for about 60% of cases.
More common in boys than in girls
Thymus contains lobules of undifferentiated
epithelial cells resembling FETAL thymus
B. Autosomal recessive inheritance
Lack of the enzyme adenosine deaminase (ADA)
leads to about 35 to 40% of cases.
ADA enzyme is involved in purine metabolism:
Deficiency results in production and accumulation
of metabolites toxic to lymphocytes
Greater decrease in cell mediated immunity than in humoral
immunity.
In the 2 variants mentioned, the thymus is small and devoid of
lymphoid cells
Very little serum IgG and virtually no IgM or IgA.
Infants develop Candida skin rashes and thrush, persistent
diarrhea, severe respiratory tract infections with
Pneumocystis carinii
Soon after birth, and failure to thrive after 3 months of age.
Wiskott-Aldrich Syndrome
X-linked recessive pattern
Defective gene located on the short arm of the X
chromosome (Xp11.23)
Wiskott-Aldrich syndrome protein (WASP)
o Located on Xp11.23
o Link membrane receptors to cytoskeletal elements.
o Maintains integrity of the cytoskeleton and signal
transduction.
Characterized by thrombocytopenia and eczema.
Circulating platelets markedly decreased.
T lymphocytes exhibit:
o Cytoskeletal disorganization
o Loss of microvilli by electron microscopy,
o Express little CD43 by immunohistochemical staining.
Usually with a normal level of serum IgG, decrease in IgM,
and elevated IgA and IgE.
Disease in early childhood: Recurrent bacterial infections,
particularly to encapsulated bacteria (Streptococcus
pneumonia)
Failure of T lymphocyte function may predispose to:
o Recurrent herpetic infections
o Pneumocystis carinii
o Pneumonia.
Bleeding problem may result from the severe
thrombocytopenia
Patients are prone to develop malignant lymphomas.
Pathology 5 | 9
 Ataxia-Telangiectasia
Genetic defect present on the long arm of chromosome 11:
o Predisposes to chromosome breakage and
rearrangement, particularly on chromosomes 7 and 14
o High risk for neoplasia
o Marked sensitivity to radiation
Quite rare and has an autosomal recessive pattern of
inheritance.
Triad of progressive cerebellar ataxia,
mucocutaneoustelangiectasias, and recurrent respiratory tract
infections with a variety of bacterial and fungal organisms
Immunoglobulin deficiencies, particularly IgA and/or IgE, may
be present, though serum IgM is usually elevated.
Symptoms usually begin between 9 months and 2 years of
age.
Selective IgA Deficiency
Affects about 1 in 600 persons of European descent
Serum IgA Secretory IgA
Familial, or acquired in association with toxoplasmosis,
measles and some other viral infection.
IgA
o Major Ig in secretions
o Mucosal defenses are weakened and infections occur in
GIT, respiratory and urogenital tracts.
Patients have a high frequency of respiratory tract allergy and
a variety of autoimmune diseases, particularly systemic lupus
erythematosus and rheumatoid arthritis
Increased frequency of infections and increased absorption of
foreign protein Ags trigger abnormal immune response.
Results from failure of the IgA type of B lymphocytes to
transform into plasma cells capable of producing IgA or from
impaired survival of IgA producing plasma cells
About half of IgA deficient persons develop anti-IgA
antibodies of the IgE type, so that transfusion of blood
products containing serum with normal IgA levels leads to
severe systemic anaphylaxis
Those with selective IgA deficiency are also deficient in IgG 2
and IgG4.
Atopy, as demonstrated by asthma, can be present.
Other Primary Immunodeficiency Disorders
Deficiencies of other components of the immune system are
uncommon.
Some of the best known are:
A. Complement component deficiencies
1. C2 deficiency
Carries a risk for development of autoimmune
disease.
No increase in susceptibility to infections.
2. C3 deficiency
Associated with recurrent and pyogenic
bacterial infections.
Increased incidence of immune-complex
mediated glomerulonephritis.
3. C5,6,7,8,9 deficiency
Increased susceptibility to recurrent Neisserial
infections
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4. C1 inhibitor deficiency
Causes hereditary angioedema
Autosomal dominant disorder
C1 inhibitor Protease inhibitor whose target
enzymes are C1r and C1s, Factor XII and the
kallikrein system. Unregulated activation of
these pathways causes bradykinin secretion.
Result in life-threatening asphyxia or nausea,
vomiting and diarrhea.
5. Complement regulatory proteins deficiency
Decay accelerating factor and CD59 deficiency
causes paroxysmal nocturnal hemoglubinuria.
In the absence of these proteins, complement
deposited on red cells are not controlled which
causes hemolysis and hemoglobinuria.
B. Chediak-Higashi syndrome:
A rare autosomal recessive disorder in which
peripheral blood neutrophils, monocytes, and
lymphocytes contain giant cytoplasmic granules
Patients have leukopenia, making them susceptible to
bacterial and fungal infections of skin, mucous
membranes, and respiratory tract
C. Chronic granulomatous disease:
Neutrophils and monocytes lack the enzyme NADPH
oxidase which is needed to generate intracellular
oxidants that destroy phagocytosed infectious
organisms, particularly catalase-positive agents such
as Staphylococcus aureus, Candida, and Aspergillus
Chronic infections are common
Acute Immunodeficiency Syndrome (AIDS)
Caused by the retrovirus Human Immunodeficiency Virus
(HIV)
Profound suppression of T cell mediated immunity
Opportunistic infection
Secondary neoplasm
Neurologic diseases
Transmission of HIV
A. Sexual contact
Predominant mode of infection
Most sexual transmission occurs among homosexual men
Virus is carried in the semen and enters the recipients
body through abrasions in rectal or oral mucosa or direct
contact with mucosal lining cells.
Viral transmission occurs in two ways:
1. Direct inoculation into blood vessels breached by
trauma
2. Into dendritic cells or CD4 cells within the mucosa
B. Parenteral innoculation
Occurred in three groups of individuals:
1. IV drug abusers
2. Haemophiliacs who received factor VIII concentrates
3. Random recipients of blood transfusion
Sharing of needles, syringes contaminated with HIV-
containing blood
C. Vertical transmission:
90% of children with AIDS have an HIV infected mother
Major cause of pediatric AIDS
Infected mothers can transmit infection to their offspring in
3 routes:
In utero by transplacental spread
During delivery through infected birth canal
After birth by ingestion of breast milk
Pathology 6 | 9
 5 Major Risk Groups in the USA Specific Binding sites
Homosexual/Bisexual men: 42% Between antigenic site gp120 of the virus and CD4 receptor
Intravenous drug users:25% T helper lymphocyte
Hemophiliacs: 0.5% Monocyte
Blood/component recipients: 1% of all patients excluding Lymphocyte
hemophiliacs Dendritic cells
10% of Pediatric AIDS patients received blood or blood gp120 must also bind to other cell surface molecules (Co-
products before 1985 receptors: Chemokine receptors) for cell entry:
CCR5
Other Risk Groups Patients CXCR4
Medical and paramedical professionals
OFW Life Cycle of HIV
Commercial Sex Workers 1. Infection of cells by HIV
Sea Men HIV infect cells by utilizing CD4 molecule as receptor,
however binding of HIV gp120 must also bind to other cell
Pathogenesis of HIV surface molecules as co receptors: CCR5, CXCR4
R5 (dominant/M tropic) strains of the virus use CCR5
X4 strains use CXCR4
R5X4 are dual tropic.
a. Initial step in infection: Binding of gp120 envelope
glycoprotein to CD4 molecules leading to a
conformational change that result to formation of
new recognition site on gp120 for the co-receptors
b. Binding of co-receptors induces conformational
change in gp41 resulting to exposure of fusion
peptide at the tip of gp41.
c. Fusion peptide inserts into cell membrane of target
cells.
d. Virus core containing HIV genome enters cytoplasm
of cell
2. Viral replication
Virus undergoes reverse transcription leading to synthesis
of double- stranded complimentary DNA (cDNA, proDNA)
In quiescent T-cells HIV cDNA remain in the cytoplasm
In dividing T-cells circularizes, enters the nucleus, and is
integrated into the host genome

Fig. 12. Pathogenesis of HIV 1 Infection

Two Major Targets of HIV Infections

1. Immune system
Profound immune deficiency, primarily affecting cell-
mediated immunity, is the hallmark of AIDS
As HIV enters the body through mucosal tissues and
blood, it first infects the following cells:
T Helper lymphocytes Severe loss of CD4+ cells
and impairment of function
Macrophage
Monocytes
Fig. 13. Life Cycle of HIV
2. Central Nervous System
HIV is carried into the brain by infected monocytes. Evidences demonstrating Importance of HIV binding to co-
Neurologic deficit caused indirectly by viral products and receptors
by soluble factors (IL-1, TNF, IL-6) produced by infected 1. Engineered non lymphoid cells for CD4 without co
microglia. receptors cannot be infected with HIV
Direct damage to neurons by soluble HIV gp120 has 2. Chemokinessterically hinder HIV infection of cells in
been postulated culture by occupying their receptors.
Dendritic cells 3. Mutation of CCR5 renders individuals resistant to HIV
infection (homozygotes)

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 Table 1. Major Abnormalities of Immune Function in AIDS

LYMPHOPENIA
Predominantly caused by selective loss of the CD4+ helper T-
cell subset
DECREASED T-CELL FUNCTION IN VIVO
Preferential loss of activated and memory T-cells
Decreased delayed-type hypersensitivity
Susceptibility to opportunistic infections and to neoplasm
ALTERED T-CELL FUNCTION IN VITRO
Decreased proliferative response to mitogens, alloantigens,
and soluble antigens
Decreased cytotoxicity
Decreased helper function for B-cell antibody production
Decreased IL-2 and IFN-y production
POLYCLONAL B-CELL ACTIVATION
Hypergammaglobulinemia and circulating immune complexes
Fig 14. Mechanism of HIV entry into host cell Inability to mount de novo antibody response to new antigens
Poor responses to normal B- cell activation signals in vitro
ALTERED MONOCYTE OR MACROPHAGE FUNCTIONS
Decreased chemotaxis and phagocytosis
Decreased class II HLA expression
Diminished capacity to present antigen to T-cells

Pathogenesis of CNS Infection

Macrophages and microglia are the predominant cell types in
the brain that are infected with HIV
Infected monocytes carry HIV into the brain
Viral products and soluble factors produced by infected
microglia are the culprits for the severity of the symptoms:
a. IL-1, TNF, and IL-6
b. Nitric Acid produced by gp41
c. Direct damage of neurons by soluble HIV gp120
d. Neurotoxins trigger excessive entry of Ca + in neurons
e. Through glutamate activated ion channels
Fig. 15. Mechanism of CD4 cell loss in HIV
Three Phases Reflecting Dynamics of Virus-
Mechanism of T-Cell Immunodeficiency in HIV Host Interaction
Productive infection of T cells and viral replication in infected 1. Acute Retroviral Syndrome
cells is the major mechanism by which HIV causes lysis of 40 to 90% develop the viral syndrome
CD4+ T cells Occurs 3 to 6 weeks after infection and resolves
o Approximately 100 B new particles are produced/day spontaneous in 2 to 4 weeks.
o 1-2B CD4+ cells die/day High virus production
Viremia
Mechanisms Causing T-Cell Destruction Widespread seeding of lymphoid tissue
Other than Direct Cytopathic Lysis Associated with self- limited acute illness with nonspecific
1. Destruction of RES cells (spleen, lymph nodes, tonsils) symptoms (Resembling a flulike syndrome):
2. Apoptosis due to chronic cell activation via activation- Sore throat
induced cell death Myalgias
3. Loss of immature precursors of CD4 t cells by direct Fever
infection of thymic progenitor cells or by infection of Weight loss
accessory cells that secrete cytokines essential for CD4+ T Fatigue
cell maturation Clinical features:
4. Fusion of uninfected and infected cells with the formation of Sore throat
syncitia (giant cells) Myalgias
Rash
HIV Infection of Non-T Cells Cervical adenopathy
In addition to CD4+ T cells, infection of macrophages and Diarrhea
follicular dendritic cells contained in the lymphoid tissues are Vomiting
also major sites of HIV infection and persistence.
Note:
Viral load at the end of the phase reflects the equilibrium
reached between the virus and the host response.
Extent of viremia, measured as HIV-1 RNA levels, useful
surrogate marker of HIV disease progression and is of
clinical value in the management of people with HIV
infection
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2. Middle Chronic Phase
7 to 10 years, intact immune system
Lymph nodes and spleen are sites of continuous HIV
replication and cell destruction
Containment of the virus
Few or no clinical manifestations of HIV infection are
present, so this phase is called Clinical Latency Period
Number of circulating blood CD4+ T cells steadily
declines
Either asymptomatic or persistent generalized
lymphadenopathy
Minor opportunistic infections: Thrush, herpes zoster
Persistent lymphadenopathy with significant constitutional
symptoms(fever, rash, fatigue) reflects onset of immune
system decompensation, escalation either asymptomatic
or persistent generalized lymphadenopathy of viral
replication and onset of crises phase
3. Final: Full Blown or Progression to AIDS
Breakdown of host defences
Increase in plasma virus and severe life threatening
clinical disease
Fever of more than 1 month duration, fatigue, weight loss
and diarrhea
Serious opportunistic infections, secondary neoplasms, or
clinical neurologic disease
AIDS indicator diseases
CDC Classification of HIV Infection
CD4+ greater than or equal to 500 cell/ul
200 to 499 cells/ul
Fewer than 200 cells/ul
Blood CD4+ counts is the strongest indication of disease
progression
AIDS-Defining Opportunistic Infections
1. Protozoal and Helminthic Infections
Cryptosporidiosis or isosporidiosis(Enteritis)
Pneumocytis (pneumonia or disseminated infection)
Toxoplasmosis (pneumonia or CNS infection)
2. Fungal Infections
Candidiasis (esophageal, tracheal, pulmonary)
Cryptococcosis (CNS Infection)
Coccidioiodomycosis (disseminated)
Histoplasmosis (disseminated)
3. Bacterial Infections
Mycobacteriosis (atypical)
M. Avium Intracellular, disseminated or
extrapulmonary
M. tuberculosis Pulmonary or extrapulmonary
Nocardiosis (pneumonia, meningitis, disseminated)
Salmonella infections, disseminated
4. Viral Infections
Cytomegalovirus(pulmonary, intestinal, retinitis, CNS)
Herpes simplex virus (localized or disseminated)
Varicella-zoster virus (localized or disseminated)
Progressive Multifocal leukoencephalopathy
Neoplasms
1. Kaposi Sarcoma
KS herpes virus (KSHV) or human herpes virus 8
Most common neoplasm in patients with AIDS
Composed of mesenchymal cells and proliferation of these
cells are driven by cytokines and growth factors that are
derived from tumor cells and HIV-infected cells.
Characterized by spindle-shaped cells that express
markers of both endothelial (vascular or lymphatic) and
smooth muscle cells.
Profusion of slit-like vascular spaces, suggesting that
lesion arises from mesenchymal precursors.
2. B Cell Non-Hodgkin Lymphoma
Vast majority of AIDS associated lymphoma
3. Primary Lymphoma Of The Brain
AIDS-defining tumor
AIDS-related disease
Noted in 20% of HIV infected pts who dev. Lymphomas
1000 times more common in patients with AIDS than the
general population
Note:
Half of the systemic B cell lymphomas and virtually all
lymphomas primary in the central nervous system are latently
infected with EBV
4. Invasive Cancer Of The Uterine Cervix
Related to human papilloma virus infection
REFERENCES
Robbins Pathologic Basis of Disease: Disease of
Immunity
2013B Trans: Immunopathology
Dr. Cus Lecture
REVIEW QUESTIONS
1. Cross-reaction with a hapten on an infectious agent that is
similar to tissue proteins--classic for post-streptoccocal
glomerulonephritis and rheumatic heart disease.
2. Positive in Anti-Smith antibody
3. A diagnosis of limited sclerosis or CREST syndrome is
associated with this antibody
4. An autoimmune disease that have vasculitis in muscle and
skin due to antibody-antigen complex
5. Where is the GENETIC defect in Brutons
agammaglobulinemia?
6. What is the mode of inheritance in Wiskott-Aldrich
Syndrome?
7. The predominant mode of transmission of HIV infection
8. The gp120 must also bind to other co receptor, CCR5 and
____
9. What phase of HIV infection there is high virus production in
the blood
10. Most common neoplasm in HIV infection
REMARKS/ANSWERS
Dr. Cu said that dont forget
to study the mode of
inheritance of each
immunodeficiency syndrome
and their genetic mutation.
She said that she will include
that in our exam. Study well
guys!

SECTION B UERMMMC Class 2014 Pathology 9 | 9