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
 T LYMPHOCYTES
-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 stimulation 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) Tcell 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 B-cells,
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
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 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
-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
-Are a 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 about 10% 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
-they are 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

IMMUNE MECHANISMS OF TISSUE INJURY
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-the 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 response can cause tissue-damaging reactions resulting in tissue injury
two different processes can be distinguished:


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
 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 (anphylactic type)
-is a rapidly occurring reaction that is mediated by IgE antibodies
-reaction can be localized or generalized
-the immune reaction is immediate- it causes a release of histaminevasodilation and smooth muscle contraction
-the 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
the 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
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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 reaction- known
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
 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
- the 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
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-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 depositedusually 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 hoursskin 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 diseaseimmune 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:
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 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
-the 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 a 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,
-upon intracutaneous injection of tuberculin into such sensitized individual, the
memory T cells interact with the antigen on the surface of antigen-presenting
cells- secretion of cytokines, that are responsible for the expression of delayed
hypersensitivity reaction
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 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 transplants 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- the speed of evolution of the response
HISTOCOMPATIBILITY SYSTEM
- most important histocompatibility antigens are grouped in HLA system -HLA =
human leukocyte antigen- the initials “HLA” stand for
“human leukocytic
antigen”
- HLA antigens are highly polymorphic- innumerable combinations of antigens can
exist- each individual has his own antigenic characteristics
- major physiologic function of HLA antigens is to present antigens to Tlymphocytes
-histocompatibility antigens were identified as antigens that evoke rejection
of transplanted organs
there are three major classes- based on their chemical structure, tissue
distribution and functionclass I antigens: present on virtually all nucleated cells and platelets
-polymorphic heavy-chain glycoproteins
class II antigens: characteristically confined to antigen-presenting cells, such as
dendritic cells, macrophages, B cells, and activated T cells
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class III proteins: some components of the complement system, some cytokines,
such as TNF., are closely linked to class I and II antigens, but are not
histocompability antigens themselves
-HLA antigens- were discovered in the course of transplantation studiesHLA antigens of the graft evoke both humoral and cell-mediated response which
may lead to graft destruction
TRANSPLANT REJECTION.
(1) T-cell mediated rejection- Tcells react to HLA antigens in the graft,
-this process involves delayed hypersensitivity and T cell-mediated cytotoxicity
-the 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)
(2) antibody-mediated rejection- although T cells are most important in
transplant rejection, antibodies also mediate rejection in two possible
ways
 as 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 circumstance, rejection occurs immediately after transplantation,
within few minutes
-the circulating antibodies react rapidly on the vascular endothelium of the
grafted organ- inflammation of vessels, thrombosis and necrosis occur
 as 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
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PREVENTION AND TREATMENT OF AUTOGRAFT REJECTION
-includes strategies how to prevent graft rejection
 reduce graft immunogenicity by:
-ensuring ABO compatibility
-better matching class I and class II HLA in donor and recipient –would improve
graft survival
 immunosupression of recipient- is a practical necessity in all organ
transplatations except in case of HLA identical twins
the drugs used include
-corticosteroid
-drugs, such as cyclosporin A- blocks
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
definitely
improves
graft
survival
but
immunosupressed 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
 HYPERACUTE REJECTION
-occurs when the recipient has been previously sensitized to antigens in graftblood transfusions, previous pregnancy, infections with HLA cross-reactive
microorganisms, etc
-occurs within minutes and hours after transplantation-immediate response in
which preformed circulating antibody fixes to antigens in graft vascular liningendothelia
-widespread acute arteriolitis and arteritis- causes thrombosis of vessels and
ischemic necrosis
virtually all arterioles exhibit characteristic fibrinoid necrosis
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- 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
 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
-cellular reaction reveals a heavy interstitial infiltrate mostly composed of small
and medium-sized lymphocytes
 acute cellular rejection
- causes a rapid failure of renal functions
- is characterized by an interstitial mononuclear cell infiltrate (macrophages,
plasma cells, T-lymphocytes)
histologically:
-edema
-interstitial hemorhages
-infiltrate composed of mainly medium-sized and small lymphocytes (both
CD4 and CD8 cells) with scattered plasma cells
 acute humoral rejection- has the form of acute rejection vasculitis - may be
present in acute reaction after transplantation or when immunosupression is
discontinued
histologically:
-necrotizing arteritis with endothelial necrosis,
-neutrophilic infiltration
-deposits of IgGs, complement and fibrin
-thrombosis and extensive cortical infarctions
more common is so called subacute vasculitis-typically occurs in the first few months after transplantation, produces
repeated attacks of clinical rejection
-microscopically is characterized by marked thickening of the intima due to
proliferating fibroblasts, macrophages and myofibroblasts
most cases can be treated by immunosupression
 CHRONIC REJECTION
-occurs over months to years and is characterized by progressive organ
dysfunction
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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
-is a transplantation of donor´s hematopoetic cells
-is used as a form of therapy of some types of hematologic malignancies- such
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
-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
 BONE MARROW TRANSPLANTATION -AUTOLOGOUS
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-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
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
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
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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- anti-neutrophil
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 origin- on
the other hand- most viral, fungal and protozoal infections are handled well
because cytotoxic T-cell mediated response is normal
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 B-cells
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-
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-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
-the 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
can be seen in patients secondary to the use of immunosupressive drugs
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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
 homosexual and bisexual men- still account for majority of cases
 intravenous drug abusers, they represent the majority of cases among
heterosexuals
 hemophiliacs, especially those who received large amounts of blood
concetrates before 1985
 chronic recipients of blood and blood components
 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
-the 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
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ad 1) immunopathogenesis of HIV disease
the hallmark of AIDS- profound immunosupression, primary affecting cellmediated immunity
-severe loss of T-cell CD4 +(helper) as well as impairment of the
function of surviving CD4 +T-cells
-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
ad 2 ) 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
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
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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 diarrhoea
-reduction of CD4 count
 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 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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