DISORDERS OF IMMUNE SYSTEM. TRANSPLANTATION.
AUTOIMMUNE DISEASES. IMMUNODEFICIENCIES. AIDS.
THE IMMUNE SYSTEM.
 Natural immunity- includes intact skin and mucosal surfaces, cellular
barriers, such as alveolar macrophages, neutrophils, acidity of the
stomach
provides
hostile
microenvironment
which
kill
many
microorganisms- these barriers are not specific against any one particular
insult, but they provide an effective first line of defence
 Adaptive immunity-is specific to the foreign substance
 CELLS OF THE IMMUNE SYSTEM
-lymphocytes are central to the adaptive immune response- two main types
of lymphocytes- B-cells and T-cells -both types of lymphocytes are derived
from precursors in the bone marrow
-B cell maturation occurs in the bone marrow, whereas T cells migrate
to the thymus for maturation
 -T LYMPHOCYTES are the mediators of cellular immunity and are
essential for induction of humoral immunity to most of antigens.
-they are found in paracortical areas of lymph nodes and periarteriolar
sheaths of the spleen
-they circulate in peripheral blood (60-70% of PB lymphocytes)
T cells-have a surface antigen recognition system known as T
cell receptor (TCR) system, each T lymphocyte has genetically programmed
specific cell surface receptor
-each T cell has unigue TCR, thus it is possible to distinguish
polyclonal (non-neoplastic) T-cell proliferations from monoclonal (neoplastic)
T-cell proliferations
-all Tcells express CD3 antigen, in addition T cells also express
other function-associated antigens, such as CD4 and CD8
-CD4+ T cells are called ”helper” T cells- they secrete cytokines
by which Helper cells influence all other cells in immune systém, such as Bcells, macrophages, and CD+8 T cells
-the central role of CD4+ cells is best seen in their absence because of HIV
infection
CD8+ T cells are called ”killer cells”- they can secrete cytokines,
but their major function is to kill virus-infected or tumor cells by direct
toxicity- process known as cellular immunity
 B LYMPHOCYTES
-B lymphocytes constitute 10-20% of circulating lymphocytes in
peripheral blood
-they are present in bone marrow, they occupy cortex of lymph nodes,
white pulp in the spleen, they are found in tonsils, and in extranodal
lymphatic tissue, such as GIT
-upon antigenic stimulation B cells form plasma cells that secrete
immunoglobulins- they are mediators of humoral immunity
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-each B cell has unique cell surface receptor with unique antigen specificity,
derived from somatic rearrangements of immunoglobulin genes
-thus, the presence of rearranged immunoglobulin genes in lymphoid cell is
used a molecular marker of B-lineage
 MACROPHAGES
- part of mononuclear phagocyte system, that plays major role in chronic
inflammation
- macrophages play important role in immune response
- they present the antigen to immunocompetent T cells (role of class
II MHC antigens- major histocompatibility complex), this process of
presentation is necessary for cell-mediated immunity, T cell cannot
be triggered by free antigens!!
- They produce cytokines, which in they control the functions of B
and T cells, endothelial cells and fibroblasts
- Macropahges produce cell-toxic metabolites and proteolytic
enzymes by which they can destruct tumor cells
- Have major functionin certain forms of cell-mediated immunity,
such as delayed hypersensitivity reaction
 NATURAL KILLER CELLS (NK)
-these cells make up about10% of the peripheral blood lymphocytes- they do
not have T-cell receptors
-they are larger than other lymphocytes, contain cytoplasmic granules
-they have ability to kill tumor cells and virus-infected cells without previous
sensitization
- CD3 negative, and CD16 and CD56 positive
-NK cells have ability to damage IgG-coated target cells-this is known as
antibody-dependent cell-mediated cytotoxicity
-NK cells can secrete cytokines, such as interferon-gama
-normal immune system is designed to enable the body to deal with foreign
substances which would cause tissue damage and disease
-however, sometimes the immune reactions themselves may cause injury of
its own tissues
 IMMUNE MECHANISMS OF TISSUE INJURY
-immune response can cause tissue-damaging reactions resulting in tissue
injury injury,
-there are two different processes:
 hypersensitivity- where the host tissue is destroyed during immune
response
 autoimmunity, where the immune system fails to distinguish between
self and non-self antigens
HYPERSENSITIVITY
-is a process whereby the host tissue is injured during an immune
response to a foreign antigen, hypersensitivity diseases are best classified on
the basis of the immunologic mechanism mediating the disease
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 in type I disease-immune response releases vasoactive amines
derived from mast cells and basophils affecting vascular
permeability and smooth muscles in various organs,
eosinophils have also great role
 in type II disease- humoral antibodies participate directly in
injuring cells by predisposing them to phagocytosis or to lysis
 in type III disease-they are ”immune complex diseases”,
humoral antibodies bind antigens and activate complement.
The fractions of complement attract neutrophils, activated
complement and release of leukocytic enzymes produce tissue
damage
 in type IV disease- cell-mediated immune response with
sensitized lymphocytes cause tissue injury
 TYPE I HYPERSENSITIVITY (anaphylactic type)
-is a rapidly occurring reaction that is mediated by IgE antibodies
-reaction can be localized or generalized
-immune reaction is immediate- it causes a release of histaminevasodilation and smooth muscle contraction
-sequence of events in the pathogenesis of this form of hypersensitivity
disorder – begins with the initial exposure to antigen (allergen) – the
pathogenetic mechanism is the same in localized and generalized reactions
- allergen stimulates the induction of CD4+ T cells – the cytokines
produced by them stimulate IgE production by B cells, act as a growth factor
for mast cells and recruit and activate eosinophils
-IgE is bound to the surface of mast cells and basophils- which have
specific receptors-this binding has high affinity-leads to degranulation of
mast cells- release of histamine- vessel dilation and smooth muscle
contraction- this important in pathogenesis of astma
-localized- the most common examples are -astma, hay fever, urticaria
(hives)
local reactions occur on the skin or mucosal surfaces
susceptibility to this type of hypersensitivity appears to be genetically
controlled- the term ”atopy” is used to imply a familial predisposition ( higher
than normal levels of IgE???)
-generalized -rarely, antigens enter the bloodstream of a sensitised individual
and bind IgE on circulating basophils- this can lead to a severe reactionknown as anaphylaxis- characterized by acute bronchospasm, circulatory
collapse and shock as a result of peripheral vasodilatationanaphylactic shock may lead to death within minutesexamples of systemic anaphylaxis include:
-parenteral administration of protein antigens , such as antisera
and drugs, such as penicillin or bee stings- can initiate anaphylaxis
-within minutes after exposure- itching, hives and skin erythema appear,
followed by striking respiratory difficulty
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 TYPE II HYPERSENSITIVITY.
In type II hypersensitivity, antibodies are formed against target
antigens that are either normal or altered cell membrane components
Three different antibody-dependent mechanisms are involved
1. Complement-mediated reaction: antibody reacts with
surface antigen, leading to fixation of complement and cell
lysis.
-blood cells are most commonly damaged by this mechanism, this occurs in the following
situations:
-in transfusion reaction, in which RBCs from incompatible donor are
destroyed after being coated by antibodies normally produced by recipient
(antibodies against ABO blood group antigens)
-in rhesus factor incompatibility-in which Rh-negative mother is
sensitized by red cells from Rh+ baby. The maternal Rh antibodies can cross
the placenta and cause destruction of Rh+ fetal red blood cells. This is called
hemolytic disease of the newbornrhesus (rh) blood group is present in about 85% of population
-rhesus antigen is inherited by a mendelian pattern of inheritence through a
dominant gene
- first Rh+ baby from the rhesus-negative mother is usually normal
(low level of antibodies), but next Rh+ babies from a sensitized mother will
develop hemolytic disease
-in autoimmune hemolytic anemia- some persons develop antibodies
against their own blood elements
2. Antibody-dependent cell-mediated cytotoxicity: this is the
second mechanism of hypersensitivity type II.
-many cells, such as NK cells, macrophages, neutrophils, and eosinophils, have receptors
for Fc portion of IgG and can cause the lysis of target cells coated with IgG antibody.
3. Antibody-mediated cellular dysfunction: in some cases,
antibodies directed against cell surface receptors impair the
function
- for example, in myasthenia gravis antibodies reactive with acetylcholine receptors in the
motor end plate of skeletal muscles, thus cause muscle weakness
 TYPE III HYPERSENSITIVITY (immune complex disease)
-in type III hypersensitivity, the antibodies react with antigens and
form antigen-antibody complexes that can be deposited either locally or at
distant sites
-the immune complexes cause tissue damage when they are
deposited-usually in blood vessel walls- they induce inflammatory reactions
-localised immune complex disease- Arthus reaction
-is an example of immune complex damage following injection the antigen
into the skin of an individual with high levels of preformed antibody
-within 2-8 hours- a hemorhagic edematous reaction occurs- after 12-24
hours- skin necrosis occurs as a result of localised vasculitis from immune
complex deposition- histologically there is an acute inflammatory reaction
with numerous neutrophils
-systemic immune complex disease-
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immune complexes are formed in the circulation and are systemically
deposited
 Acute serum disease- is the prototype caused by large amounts of
foreign serum
For example- it used to be frequent complication of administration of horse anti-tetanus
serum
-Now it is seen infrequently, for instance in patients treated with horse
anti-thymocyte globulin for treatment of aplastic anemia- about 5 days after
the serum inoculation – antibodies directed against the serum components
are produced , these are complexed with antigen still present in the
circulation- and these immune complexes are deposited in the tissues
-the factors that determine that the complexes are deposited in the
tissues are as follows:
 Size of the complexes seems to be important
-Very large immune complexes formed in great antibody excess are readily
cleared from circulation by macrophage phagocytosis and are therefore
harmless
-small or intermedite size complexes are more dangerous- they circulate
longer, and bind less to phagocytic cells
for the reasons not entirely clear, the favourite sites for deposition of immune complexes
are kidneys, heart, joints, skin, small vessels—once complexes are deposited, they initiate
acute inflammatory reaction and cause tissue damage
-typical example of systemic immune complex disease, is post-streptococcal
glomerulonephritis
 TYPE IV HYPERSENSITIVITY.
-is mediated by T lymphocytes rather than by antibodies
-there are two types of reactions mediated by different subsets of
lymphocytes
1. delayed type hypersensitivity, initiated by CD4+ T cells
2. cellular cytotoxicity, mediated by CD8+ T cells
 DELAYED TYPE HYPERSENSITIVITY
- classic example is Mantoux reaction- tuberculin test
- antibodies are not involved, reaction is delayed at least 12 hours
-the response is usually to viruses, fungi, protozoans and mycobacteria
-typical example of this reaction- is tuberculin test
-if small amount of protein derived from tubercle bacilli is injected into
the skin of a non-immune person- no reaction
-in contrast, in people who have already had tuberculosis or have been
immunised with BCG vaccination- red skin reaction develops within 12
hourshistologically-the tissue shows immune mediated epithelioid granuloma
composed of epithelioid macrophages, giant Langhans cells with
accumulation of lymphocytes
 -the sequence of events in delayed hypersensitivity begins with the first
exposure of the individual to tubercle bacilli- CD4+ lymphocyte recognize
antigens of bacilli, this process results in formation of sensitized CD4+ T
cells, that remain in circulation for long time,
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-upon intracutaneous injection of tuberculin into such sensitized individual,
the memory T cells interact with the antigen on the surface of antigenpresenting cells- secretion of cytokines, that are responsible for the
expression of delayed hypersensitivity reaction
 this type of hypersensitivity is amjor mechanism of defense against variety
of intracellular pathogens, such as mycobacteria, fungi, parasites, and
also is involved in transplant rejection and tumor immunity
 the central role of this type of defense is best seen in patients with AIDSloss of CD4+ means that the host response against mycobacteria, fungi,
parasites is markedly impaired
 T-CELL MEDIATED CYTOTOXICITY- in this variant , sensitized CD8+ T
cells kill antigen-coated target cells
-such effector cells are called cytotoxic T cells, they are directed against
cell surface histocompatibility antigens, play important role in transplant
rejection, and in resistance to viruses
TRANSPLANTATION.
-rejection of organ transplats is a complex immunologic phenomenon that involves
cell-mediated and antibody-mediated responses, both are targeted on the HLA antigen in the
graft
- the rejection reactions can be classified according to:
1- whether the response is cell and/or antibody mediated
2- according to speed of evolution of the response
HISTOCOMPATIBILITY SYSTEM
-the most important histocompatibility antigens are grouped in HLA system -HLA =
human leukocyte antigen-the initials “HLA” stand for “human leukocytic antigen”
-HLA antigens- were discovered in the course of transplantation
studies- HLA antigens of the graft evoke both humoral and cell-mediated
response which may lead to graft destruction
TRANSPLANT REJECTION.
1. T-cell mediated rejection- T cells react to HLA antigens in the
graft,
-this process involves delayed hypersensitivity and T cell-mediated
cytotoxicity
-generation of CD8+ cytotoxic T cells starts when recipients
lymphocytes encounter foreign HLA antigens on the surface of cells in the
graft- it is believed that the most important immunogens are dendritic cells
in the graft- direct Tcell-mediated cytolysis
-CD4+ T cells secreting cytokines are also generated- results in
delayed hypersentitivity reaction- increased vascular permeability,
microvascular injury, tissue ischemia and graft destruction
= acute rejection (10-14 days)
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2. antibody-mediated rejection- although T cells are most important in
transplant rejection, antibodies also mediate rejection in two possible
ways

1) hyperacute rejection- occurrs when preformed anti-donor
antibodies have been already present ready to use in the recipient
circulation
-may be present for example in recipient who had already rejected the organ
(kidney) before
-or had recieved blood transfusion from HLA-non-identical donors
-in such circumstances, rejection occurs immediately after
transplantation, within few minutes
-circulating antibodies react rapidly on the vascular endothelium of the
grafted organ- inflammation of vessels, thrombosis and necrosis occur

2) acute rejection in non-sensitized recipients
-caused by anti-HLA humoral antibodies
-the major target of antibody-mediated damage is vascular endotheliumimportant mechanism in mediating acute vascular rejection
 this type of rejection is iportant in recipients who have been treated
with immunosupressive drugs- these drugs have limited the T-cell
responses but formation of antibodies is not affected
PREVENTION AND TREATMENT OF AUTOGRAFT REJECTION
1. Reduce graft immunogenicity by:
-by ensuring ABO compatibility
-by better matching class I and class II HLA in donor and recipient –would
improve graft survival
2. immunosupression of recipient- is a practical necessity in all organ
transplatations except in case of HLA identical twins
 drugs used include corticosteroid, drugs, such as cyclosporin Ablocks interleukin-2 gene transcription, azathiaprine- metabolic toxin
that stops lymphocyte maturation
 anti-Tcell antibodies (for example anti-CD3 monoclonal antibodies that
react with all T cells)- allows more selective destructio of T-cells
activated by the grafted organ
immunosupression improves graft survival, but the patients are in high risk
of opportunistic infections-may die of disseminated fungal, viral or bacterial
opportunistic infections
MORPHOLOGY OF TRANSPLANT REJECTION REACTIONS
-renal transplant rejection has been described in most details, however with minor
variations, the same classification of transplant rejection reaction is valid for other organs,
such as liver, heart, etc.
We can distinguish three major types of rejection:
 hyperacute
 acute
 chronic
1. HYPERACUTE REJECTION
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-occurs when the recipient has been previously sensitized to antigens in
graft- blood transfusions, previous pregnancy, infections with HLA crossreactive microorganisms, etc
-occurs within minutes and hours after transplantation-immediate response
in which preformed circulating antibody fixes to antigens in graft vascular
lining-endothelia
-widespread acute arteriolitis and arteritis- causes thrombosis of vessels and
ischemic necrosis
virtually all arterioles exhibit characteristic fibrinoid necrosis
- deposits of IgA and IgM and complement may be demonstrated within the
blood vessel walls with endothelial injury, fibrin-platelet microthrombi and
neutrophilic infiltration
grossly: cyanotic, mottled appearance of the organ
2. ACUTE REJECTION
-occurs within a few days after transplantation or after cessation of
immunosupressive therapy
-combined process in which both cellular and humoral responses play parts
histologically:
-humoral reaction is associated with vasculitis, thrombosis and extensive
cortical infarctions
-cellular reaction reveals a heavy interstitial infiltrate mostly composed of
small and medium-sized lymphocytes
-edema, interstitial hemorhages
most cases can be treated by immunosupression
3. CHRONIC REJECTION
-occurs over months to years and is characterized by progressive organ
dysfunction
clinical presentation in renal transplantation- progressive rise in serum
creatine levels- progressive chronic renal failure
morphologically:
-vascular changes-the arteries show dense intimal fibrosis
-interstitial inflammatory infiltrate- composed of plasma cells and
lymphocytes and eosinophilic leukocytes
these cause renal ischemia- vascular atrophy ( tubular atrophy, hyalinized
glomeruli, interstitial fibrosis, shrinkage of renal parenchyma )
BONE MARROW TRANSPLANTATION - allogenic
- transplantation of donor´s hematopoetic cells
-is used as a form of therapy of some types of hematologic malignanciessuch as CML, of aplastic anemia and some severe forms of congenital
immunodeficiencies
-first- recipient is given a large doses of irradiation and cytotoxic drugs
in order to eradicate malignant cells and create a satisfactory conditions for
the graft acceptance, and in order to minimize host rejection of grafted
marrow
-however, recipients NK cells or radiation-resistent T cells may mediate
significant transplant rejection
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-there are two major problems in BMT
1) rejection of transplant
2) GVHD- graft-versus-host disease - unique problem with marrow
transplantation
GVHD- occurs when immunocompetent T- cells are transplanted to recipient
who is immunologically deficient (after heavy immunosupression )
-donor´s bone marrow immunocompetent cells recognize recipients
tissues as foreign and react against them
T-cells should be depleted from the donors bone marrow completely- to
prevent GVHD
-GVHD is a potential lethal complication
in some cases- GVHD reaction may be to some extent beneficial- used
as GVL reaction (graft-versus-leukemia) - when donor immunocompetent
cells are used to destroy leukemic cells of recipient
morphologic findings in GVHD:
epithelial cell necrosis caused by cytotoxic effect of T cells derived from the
graft occur in three major target organs: skin, liver, GIT mucosa
cause three major clinical symptoms: rashes, jaundice, diarrhea
AUTOLOGOUS BONE MARROW TRANSPLANTATION
-distinctive form of transplantation when the transplant is derived
from the same organism
autologous bone marrow transplantation is used as a form of therapy of
highly malignant progressive solid malignant tumors with high risk of
recurrences, with infaust prognosis
-if classic therapeutic approaches fail
-highly malignant tumors require very aggressive therapy- to eradicate all
malignant cells
-but BM cells are rather sensitive to radiation and cytotoxic drugs- thus
agressive therapy causes irreversible injury to BM
-BM can be removed from the body before the therapy, deeply frozen, then
given back to the same patient after cessation of the aggressive therapy - no
severe complications- no GVHD, no risk of graft rejection
AUTOIMMUNE DISEASES.
-patients with autoimmune diseases have antibodies against their own
tissues circulating in their blood- loss of self-tolerance
Self-tolerance refers to lack of immune responsiveness to the individual´s
own tissue antigens
Loss of self-tolerance underlie a group of multi-system autoimmune
diseases, such as
-systemic lupus erythematosus
-rheumatoid disease
-polyarteritis nodosa
 systemic lupus erythematosus
is a febrile inflammatory multisystem disease of protean manifestation and
variable behaviour
it is characterized by the following features
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clinically- remitting relapsing chronic disease with acute onset and it
may affect any organ, such as the skin, joints, heart, serosal membranes,
kidney
Clinical presentation of SLE is variable, and there is overlap with other
autoimmune connective tissue diseases, such as rheumatoid arthritis,
polymyositis and others
histologically- all site of involvement have in common vascular lesions
with fibrinoid deposits in the wall
immunologically-the disease involves many autoantibodies, especially
antinuclear antibodies (ANA)
SLE is more common in females, its incidence is one per 2500 persons in
certain populations- fairly common disease
 rheumatoid disease
-is a systemic chronic inflammatory disease that affects principally the
joints
disease is characterized by a nonsuppurative proliferative synoviitis, which lead to
destruction of articular cartilage and progressive disabling arthritis
-extra-articular involvement is less commonly encountered, may
involve the skin, heart, blood vessels, muscles
RA is very common condition, with prevalence about 1% in population,
women are more commonly affected
 -polyarteritis nodosa
is a disease of medium-sized and small-sized arteries characterized by acute
necrotizing inflammation of these vessels
-virtually any organ can be affected, PAN appears most often in middle-aged
adults, men more commonly affected
cause and pathogenesis of PAN remains uncertain, possible mechanism has
been recently proposed- PAN can be caused by ANCA autoantibodies- antineutrophil cytoplasmic antibodies
IMMUNODEFICIENCY DISEASE
1) primary immunodeficiencies of genetic origin
2) secondary immunodeficiencies- acquired (AIDS)
PRIMARY IMMUNODEFICIENCIES
relatively uncommon
clinical symptoms appear early after birth, affected child- extremely
vulnerable to infection- often fatal
1) BRUTON S DISEASE = congenital agammaglobulinemia
-is characterized by defect in differentiation of pre-B-lymphocytes into
mature B-lymphocytes
-one of more common causes of congenital immunodeficiencies
-it is seen almost entirely in males (X- linked inheritence) - it is usually
apparent in about six month of age of a child ( when maternal IgG of milk is
depleted )
clinically: recurrent serious infections, mostly respiratory bacterial in originon the other hand- most viral, fungal and protozoal infections are handled
well because cytotoxic T-cell mediated response is normal
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increased risk for Pneumocystis carinii
morphologically: B-cell are absent in the circulation, low serum level of IgGs
germinal centers, Payer s patches of intestine and tonsils are devoid of Bcells
remarkable absence of plasma cells
T-cell system is entirely normal
2) DI GEORGE SYNDROM (thymic hypoplasia)
-results from a lack of thymic influence on the immune system-thymus is usually rudimentary (hypoplastic)
-T-cells are deficient or even absent- from all T-cell areas in immune
system, such as paracortical regions of lymph nodes and periarteriolar zones
in spleen
-clinically -extreme vulnerability to viral, fungal and protozoal
infections
- B-cell immunity system is normal, normal formation of plasma cells,
-normal serum immunoglobulin
but susceptibility to infection caused by intracellular bacteria (mycobacteria)
is also increased- due to impaired phagocytosis- T-cell mediated signals for
activation of phagocytosis are absent
main cause of DiGeorge syndrom- is congenital malformation of third and
fourth pharyngeal pouches- result in hypoplasia or aplasia of the organs
derived of these embryonic structures, such as
thymus ( T-cell immunodeficiency)
parathyroid glands ( tetany from hypocalcemia )
developmental defects affecting face, ears, heart
3) SWISS-TYPE AGAMMAGLOBULINEMIA - severe combined immunodeficiency
-is characterized by combined T-cell and B-cell immunodeficiency most
affected children have marked lymphopenia
-thymus is always hypoplastic, or it may be totaly absent
-lymph node are almost unvisible- markedly hypoplastic
-the lymphoid tissue in tonsils, gut and appendix is hypoplastic
affected infants are vulnerable to all infections, caused by viruses, bacteria,
fungi, protozoa, most children die in the first year of life
4) ISOLATED DEFICIENCY OF IMMUNOGLOBULIN A
-is the most common primary immunodeficiency
most affected are asymptomatic, but some my experience recurrent
respiratory infections, chronic diarrhea
significantly higher risk of autoimmune diseases
in half of patients there are serum antibodies against IgA- when transfused
with the blood containing normal IgA level, some of the patients develop
severe anaphylactic reactions
SECONDARY IMMUNODEFICIENCIES.
very common- can be regularly seen in patients with malnutrition, sepsis,
chronic infections, malignant disease, such as in Hodgkin disease, many
types of cancer
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can be seen in patients secondary to the use of immunosupressive drugs
due to loss of proteins, including immunoglobulins- in nephrotic syndrom
(proteinuria due to chronic renal diseases)
ACQUIRED IMMUNODEFICIENCY SYNDROME (AIDS)
-it is an epidemic retroviral disease caused by RNA retrovirus
characterized by profound immunosupression associated with severe
opportunistic infections, secondary tumors and clinically is known as AIDS
EPIDEMIOLOGY
-AIDS first recognized in U.S in 1981 when a group of homosexual
men were noted to have an unusual lung infection-pneumocystis carinii
pneumonia,
- the pool of infected persons was shown to be in central Africa
five groups in the population at higher risk of AIDS
4. homosexual and bisexual men- still account for majority of cases
5. intravenous drug abusers, they represent the majority of cases among
heterosexuals
6. hemophiliacs, especially those who received large amounts of blood
concetrates before 1985
7. chronic recipients of blood and blood components
8. heterosexual contacts of members of groups 1-4
transmission of HIV may occur through three pathways
-sexual contacts
-parenteral inoculation (blood)
-passage of the virus from infected mother to the newborn baby
venereal transmission is by far the most common-it is believed that virus is carried in the lymphocytes present in the
sperma- the virus enters the recipient body through erosions in rectal,
vaginal, or cervical mucosa
-extensive studies indicate that HIV infection is not trasmitted by casual
personal contact, no convincing evidence of spreading by insect bites
PATHOGENESIS
-CD4 molecule of CD4+ T cells acts as a receptor for the HIV allowing
it to enter the cell
-the virus uses reverse transcriptase to produce DNA from its own RNA
-the viral DNA is then inserted into the lymphocyte´s chromosomes
-the tissue macrophages can also be infected
there are two major target system for HIV
-immune system
-central nervous system
immunopathogenesis of HIV disease
the hallmark of AIDS- profound immunosupression, primary affecting cellmediated immunity
-severe loss of T-cell CD4+ as well as impairment of the function of
surviving CD4 +T-cells
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-the CD4 molecule itself is a high-affinity receptor for HIV
it is not clear if other cells can be directly affected by HIV, such as
astrocytes, fibroblasts etc
-loss of CD4 + T cells result in the inversion of ration CD4 to CD8 in
the peripheral blood
normal CD4-CD8 ration is about 2, in AIDS patients less than 1
- pathogenesis of central nervous involvement
-the nervous system is another major target of HIV infection in
addition to lymphoid system
-macrophages and monocytes (microglia) are the predominant cells
affected by HIV in CNS
-possibly direct cytotoxic mechanism for brain injury in AIDS
MORPHOLOGICAL FINDINGS in AIDS natural history of HIV infection
In the course of HIV infection - three phases reflecting the interactions
between host and virus can be recognized
 early acute stage
 chronic middle stage
 final crisis stage
 early acute phase represents the initial response of an immunocompetent
adult individual to HIV infection,
-is characterized by transient viremia, seeding of lymphoid tissue, and
temporary fall in CD4+
- it is characterized by high levels of virus in the plasma- with rapid, highly
developed, anti-viral immune response
clinically- this phase is associated self-limited acute ilness with nonspecific
symptoms, such as fever, rash, sore throat, myalgias, and aseptic meningitis
may develop
-clinical recovery and near normal CD4 T-cell count occur within 6 to 12
weeks
 middle chronic phase represents a stage of immune containment of the
virus, the virus is still under control, the immune system is in good state,
there is continued low level replication of HIV persisting for several years
-during this phase there is continuing battle between HIV and the host immune systém,
the CD8+ T cytotoxic cells are active, the decrease in CD4+ cell in peripheral blood is
slow
patients are either asymptomatic or persistent generalized lymphadenopathy
develops
-persistent generalized lymphadenopathy with fever, rash and fatigue
represent the onset of immune failure- the onset of crisis phase
 final crisis phase is characterized by breakdown of host defense, that
results in increased viral replication, clinically is referrred to as AIDSrelated complex
followed by full AIDS- the borderline between the AIDS-RC and full AIDS is
not sharp
patients with AIDS-related complex present with:
-long-lasting fevers
-fatigue, loss of weight, chronic diarrhea
-reduction of CD4 count
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full-blown HIV infection-AIDS
- is characterized by variety of serious opportunistic infections
if these infections begin to develop- it means that the patient left AIDSrelated complex and entered fully developed AIDS
a) viral infection
-cytomegalovirus (lung, GIT, CNS infections)
herpes simplex virus (generalized)
varcella-zoster virus
b) bacterial infections
mycobacterioses
nocardiosis
c) fungal infections
candidiasis (mouth, lung,skin, disseminated)
cryptococcosis (CNS)
coccidiomycosis (disseminated)
d) protozoal infections
pneumocystis carinii (lungs,disseminated)
toxoplasmosis (disseminated, CNS)
development of malignant tumors
- Kaposi sarcoma (up to 20% of patients)
-non-Hodgkin malignant lymphoma, such as -Burkitt lymphoma- (EBV
often detected) and large cell B lymphoma
-primary lymphoma of the brain
-invasive cancer of the uterine cervix
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