the university of Georgia

Fundamentals of Pathology

Topic: Immune deficiency Diseases ( AIDS )

Dr. tamar goderidze
Arezo bahrami akbari UG: 1701818
Alaa Eid UG: 1702101

Primary (Inherited) Immunodeficiencies

Most of our physical characteristics are passed along from parents to children. Examples of these
include the color of our eyes and hair, and the proteins that determine our blood type. In the same
manner, many primary immunodeficiency diseases are inherited, or passed on, in families. The
DNA in our cells contains about 30,000 genes that are responsible for the characteristics that
make an individual unique. These genes are packaged on long, string-like structures called
chromosomes. Every cell in the body contains all the chromosomes and consequently, all of the
genes necessary for life. Each of our cells contains 23 pairs of chromosomes, hence, 23 sets of
genes. One of each pair of chromosomes is inherited from our mother while the other is inherited
from our father. Since genes are on these chromosomes, we also inherit one gene (or message)
for a certain characteristic (such as eye color) from our biological mother and one gene for the
same characteristic from our biological father. During egg and sperm production, the total
number of 46 parental chromosomes (23 pairs) is divided in half. One chromosome of each pair,
and only one, is normally passed on in each egg or sperm. When fertilization of the egg occurs,
the 23 chromosomes contained in the egg combine with the 23 chromosomes in the sperm to
restore the total number to 46. In this way each parent contributes half of their genetic
information to each offspring. All of the chromosomes except the sex chromosomes are called
autosomes and are numbered from 1-22 according to size. One additional pair of chromosomes
determines the sex of the individual. These are called the sex chromosomes and are of two types,
X and Y chromosomes. females have two X chromosomes, and males have an X and a Y
chromosome. As a result of having two X chromosomes, females can only produce eggs that
have an X chromosome. In contrast, since men have both an X and Y chromosome, half of the
sperm produced will contain an X chromosome and half will carry a Y chromosome. The sex of
the baby is determined by which type of sperm fertilizes the egg. If the sperm that fertilizes (or
combines with) the egg carries an X chromosome, the child that results will be a female. If the
sperm carries a Y chromosome, the child that results will be a male. Primary immunodeficiency
diseases are inherited genetic disorders that impair mechanisms of innate immunity (phagocytes,
NK cells, or complement) or the humoral and/or cellular arms of adaptive immunity (mediated
by B lymphocytes and T lymphocytes, respectively). These immunodeficiencies are usually
detected in infancy, between 6 months and 2 years of age, the telltale signs being susceptibility to
recurrent infections. With advances in genetic analyses, the mutations responsible for many of
these diseases are now known .
DiGeorge Syndrome (Thymic Hypoplasia)
DiGeorge Syndrome (DGS) is a primary immunodeficiency, often but not always, characterized
by cellular (T-cell) deficiency, characteristic facies, congenital heart disease and hypocalcemia.
DGS is caused by abnormal formation of certain tissues during fetal development. During fetal
development, various tissues and organs often arise from a single group of embryonic cells.
Although the tissues and organs that ultimately develop from this group of embryonic cells may
appear to be unrelated in the fully formed child, they do have a similar origin. Approximately
90% of patients with DGS have a small deletion in chromosome number 22 at position 22q11.2.
Thus another name for this syndrome is the 22q11.2 deletion syndrome. Other names include
velocardiofacial syndrome and conotruncal anomaly face syndrome.

While the genetic defect is the same in the majority of patients with DGS, they all do not present
in the same way. For example, some patients with DGS have severe cardiac anomalies; some
have none at all. Some have major learning disabilities; others have none. This is called
phenotypic variability. There is wide phenotypic variability in patients with DGS.
Patients with DGS may have any or all of the following:
Unusual facial appearance - Features may include an underdeveloped chin, eyes with heavy
eyelids, ears that are rotated back and small upper portions of their ear lobes. These facial
characteristics vary greatly from person to person and may not be prominent in many patients.
Heart defects - These include a variety of heart (or cardiac) defects. The defects usually involve
the aorta and the part of the heart from which the aorta develops. In some patients, heart defects
may be very mild or absent.
Thymus gland abnormalities - The thymus is crucial in the development of the cellular (T-cell)
immune system. It is normally located in the upper area of the front of the chest behind the
breastbone. The thymus begins its development high in the neck during the first three months of
fetal development. As the thymus matures and gets bigger, it drops down into the chest to its
ultimate location under the breastbone and in front of the heart.
The thymus controls the development and maturation of one kind of lymphocyte, the T-
lymphocyte, “T” for ”Thymus.”The size of the thymus affects the number of T-lymphocytes that
can develop. Patients with a small thymus produce fewer T-lymphocytes than those with a
normally sized thymus. T-lymphocytes are essential for protection against infections. Some T-
lymphocytes, the cytotoxic T-lymphocytes, directly kill viruses. T-lymphocytes also help B-
lymphocytes to develop into antibody producing plasma cells. Patients with DGS may have poor
T-cell production compared to their peers, and as a result, have an increased susceptibility to
viral, fungal and bacterial infections. As with the other defects in DGS, the T-lymphocyte defect
varies from patient to patient. In a very small number of patients with DGS the thymus is
completely absent, so the number of T-cells is severely low. These patients require prompt
medical attention since they are severely immunocompromised. The majority of patients with
DGS have less severe or mild deficiencies.
Autoimmunity - Patients with DGS develop autoimmune disease at a rate that is higher than in
the general population. Autoimmune disease occurs when the immune system inappropriately
attacks its own body. It is not known why this happens in people with T-lymphocyte problems.
The most common autoimmune diseases in DGS are idiopathic thrombocytopenia purpura
(antibodies against platelets), autoimmune hemolytic anemia (antibodies against red blood cells),
autoimmune arthritis, and autoimmune disease of the thyroid gland.
Parathyroid gland abnormalities - These glands may be underdeveloped in patients with DGS,
causing hypoparathyroidism. The parathyroids are small glands found in the front of the neck
near the thyroid gland, hence the name “parathyroid.” They function to control the normal
metabolism and blood levels of calcium. People with DGS may have trouble maintaining normal
levels of calcium, and this may cause seizures (convulsions). In some cases, the parathyroid
abnormality is not present at all, relatively mild or only a problem during times of stress such as
severe illness or surgery. The parathyroid defect often becomes less severe over time.
Miscellaneous clinical features - Patients with DGS may have a variety of other developmental
abnormalities including cleft palate, poor function of the palate, delayed acquisition of speech
and difficulty in feeding and swallowing. In addition, some patients have learning disabilities,
behavioral problems, psychiatric disorders and hyperactivity. For example schizophrenia occurs
at a higher rate in patients with DGS compared to the rate in the general population.
Diagnosis of DiGeorge Syndrome
The diagnosis of DGS is made on the basis of signs and symptoms that are present at birth, or
develop soon after birth, along with confirmatory genetic testing. Some infants may have facial
features that are characteristic of DGS. Affected infants may also show signs of low blood
calcium levels as a result of hypoparathyroidism. This may show up as low blood calcium on a
routine blood test, or the infant may be “jittery” or have seizures as a result of the low calcium.
Affected infants may also show signs and symptoms of a heart defect. These may include a heart
murmur that is detected on a routine physical exam. They may show signs of heart failure, or
they may have low oxygen content of their arterial blood and appear “blue” or cyanotic. Affected
infants may also develop infection because of their low T-lymphocyte levels.
In some children, all of the classical features are present and the diagnosis of DGS is made very
early. In other people, all of the different organs and tissues may not be affected, and the organs
and tissues that are involved may be impaired to different degrees so that the presentation is
more subtle and the diagnosis is not made until later on in life when a speech delay, feeding
problems or autoimmune disease are noted.
In the past, the diagnosis of DGS was usually made when all the characteristic findings described
above were present without obtaining a confirmatory genetic test. Unfortunately, this caused
many mild cases to be missed. In recent years, the genetic test has been more widely used.
Approximately 90% of patients with the clinical diagnosis of DGS have a small deletion of a
specific portion of chromosome number 22 at position 22q11.2, called a microdeletion. This is
usually identified by a blood test called a FISH analysis (for Fluorescent In Situ Hybridization).
The FISH test has made the diagnosis of DGS more precise and more common.
Approximately 90% of 22q11.2 deletions occur spontaneously and have not been passed on from
the mother or father of the child. But once the diagnosis has been made, genetic counseling is
critically important and testing should be offered to parents and other family members.
DGS is the most common microdeletion syndrome. The rate of occurrence is estimated at
approximately 1 in 4,000 people. For patients who do not have the 22q11 microdeletion, a DGS
diagnosis can still be made on the basis of the characteristic combination of clinical features and
by excluding a diagnosis of other syndromes.
Therapy for DiGeorge Syndrome
Therapy for DGS is aimed at correcting the defects in the affected organs or tissues. Therefore,
therapy depends on the nature of the different defects and their severity. In general, patients with
DGS have the same response rates to therapies as do the general population.
Treatment of the low calcium and hypoparathyroidism may involve calcium supplementation
and replacement of the missing parathyroid hormone.
A heart (or cardiac) defect may require medications or corrective surgery to improve the function
of the heart. Surgery can be performed before any immune defects are corrected. If there is a
problem with the T-cells, precautions must be taken as with other children with congenital T-cell
immunodeficiencies. These include irradiating all blood products to prevent graft vs. host disease
and ensuring the blood products are free of potentially harmful viruses.
The need for therapy of the T-lymphocyte defect varies. Most people with DGS have normal T-
lymphocyte function and do not require therapy for immunodeficiency. Other children initially
have mild defects in T-lymphocyte function that improve, as they grow older. In these cases the
small amount of thymus tissue present provides adequate T-lymphocyte function.
Management of DiGeorge Syndrome
Immunologic care for patients with DGS includes monitoring the overall immune system
including the numbers and function of T-lymphocytes. Patients who have initially been deemed
immunocompetent but then develop frequent, severe or unusual infections should have their
immune system reevaluated.
Between 1-2% of patients with DGS completely lack T-cells. This is a serious, potentially fatal,
condition that is similar to Severe Combined Immune Deficiency. This is sometimes called
“complete” DiGeorge syndrome and is usually associated with severe low blood calcium causing
seizures. In this situation, T-cells must be reconstituted for the infant to survive. This can be
achieved with a thymus transplant (available only on a research basis) or by stem cell
transplantation.
Severe Combined Immunodeficiency
Severe combined immunodeficiency (SCID) spans a constellation of genetically distinct
syndromes, all having in common impaired development of mature T lymphocytes and/or B
lymphocytes and defects in both humoral and cell-mediated immunity. Affected infants present
with thrush (oral candidiasis), severe diaper rash, and failure to thrive. Some infants develop a
generalized rash shortly after birth because maternal T cells are transferred across the placenta
and attack the fetus, causing GVHD. Children with SCID are extremely susceptible to recurrent,
severe infections by a wide range of pathogens, including Candida albicans, Pneumocystis
jiroveci, Pseudomonas, cytomegalovirus, varicella, and a whole host of bacteria. Without HSC
transplantation, death occurs within the first year of life. The overall prevalence of the disease is
approximately 1 in 65,000 to 1 in 100,000, but it is 20 to 30 times more frequent in some Native
American populations.
Despite the common clinical manifestations, of different forms of SCID the underlying defects
are quite varied. Often, the defect resides in the T-cell compartment, with a secondary
impairment of humoral immunity. Two major forms are described next.
• X-linked SCID. Approximately half of the cases of SCID are X-linked; these are caused by
mutations in the gene encoding the common γ (γc) chain shared by the receptors for the
cytokines IL-2, IL-4, IL-7, IL-9, and IL-15. Of these cytokines, defective IL-7 signaling is the
most important underlying basis of SCID because this cytokine is responsible for stimulating the
survival and expansion of immature B and T cell precursors in the generative lymphoid organs.
• Autosomal recessive SCID. Another 40% to 50% of SCID cases follow autosomal recessive
pattern of inheritance, with approximately half of these caused by mutations in adenosine
deaminase (ADA), an enzyme involved in purine metabolism. ADA deficiency results in
accumulation of adenosine and deoxyadenosine triphosphate metabolites, which inhibit DNA
synthesis and are toxic to lymphocytes. Other autosomal recessive forms of SCID result
variously from defects in another purine metabolic pathway, primary failure of class II MHC
expression, or mutations in genes encoding the recombinase responsible for the rearrangement of
lymphocyte antigen-receptor genes. Currently, HSC transplantation is the mainstay of treatment.
X-linked SCID is the first disease in which gene therapy has been successful. For gene therapy, a
normal γc gene is expressed using a viral vector in HSCs taken from patients, and the cells are
then transplanted back into the patients. The clinical experience is small, but some patients have
shown reconstitution of their immune systems for several years after therapy. Unfortunately,
however, about 20% of patients receiving a first-generation viral vector developed T cell acute
lymphoblastic leukemia (T-ALL), highlighting the dangers of this particular approach to gene
therapy. The uncontrolled T-cell proliferation is likely the result of the virus integrating into the
genome close to an oncogene, leading to the activation of the oncogene, and possibly also
because of the growth advantage conferred by the introduced normal γc gene. Current trials are
using new vectors with safety features built in. Patients with ADA deficiency also have been
treated with HSC transplantation and, more recently, with administration of the enzyme or gene
therapy involving the introduction of a normal ADA gene into T-cell precursors.
Secondary (Acquired) Immunodeficiency
Secondary (acquired) immune deficiencies may be encountered in individuals with cancer,
diabetes and other metabolic diseases, malnutrition, chronic infection, and in patients receiving
chemotherapy or radiation therapy for cancer, or immunosuppressive drugs to prevent graft
rejection or to treat autoimmune diseases .As a group, the secondary immune deficiencies are
more common than the disorders of primary genetic origin. Discussed next is perhaps the most
important secondary immune deficiency disease, AIDS, which has become one of the great
scourges of humankind. AIDS is a disease caused by the retrovirus human immunodeficiency
Virus (HIV) and is characterized by profound immunosuppression that leads to opportunistic
infections, secondary neoplasms, and neurologic manifestations. Although AIDS was first
recognized as a distinct entity as recently as the 1980s, it has become one of the most devastating
afflictions in history. Effective anti-retroviral drugs have been developed.
Epidemiology
Epidemiologic studies in the United States have identified groups of adults at high risk for
developing AIDS.1, Homosexual or bisexual men constitute the largest Group2, Heterosexual
contacts of members of other high-risk groups. Women who are infected by male partners.3,
Intravenous drug abusers with no previous history of homosexuality 4, Surviving hemophiliacs,
especially those who received large amounts of factor VIII or factor IX 5, HIV infection of the
newborn.
Properties of HIV: HIV is a nontransforming human retrovirus belonging to the lentivirus
family. Included in this group are feline immunodeficiency virus, simian immunodeficiency
virus, visna virus of sheep, bovine immunodeficiency virus, and the equine infectious anemia
virus. Two genetically different but related forms of HIV, called HIV-1 and HIV-2, have been
isolated from patients. HIV-1 is the most common type associated with AIDS in the United
States, Europe, and Central Africa, whereas HIV-2 causes a similar disease principally in West
Africa and India. The ensuing discussion relates primarily
Structure of HIV: Similar to most retroviruses, the HIV-1 virion is spherical and contains an
electron-dense, cone-shaped core surrounded by a lipid envelope derived from the host cell
membrane. The virus core contains (1) the major capsid protein p24; (2) nucleocapsid protein
p7/p9; (3) two copies of viral genomic RNA; and (4) the three viral enzymes
Pathogenesis of HIV Infection and AIDS: While HIV can infect many tissues, the two major
targets of HIV infection are the immune system and the central nervous system.
Life Cycle of HIV:The life cycle of HIV consists of infection of cells, integration of the provirus
into the host cell genome, activation of viral replication, and production and release of infectious
virus .
Infection of Cells by HIV: HIV infects cells by using the CD4 molecule as a receptor and
various chemokine receptors as coreceptors. Binding of HIV gp120 to CD4 is essential for
infection and accounts for the tropism of the virus for CD4+ T cells and for CD4+
monocytes/macrophages and DCs. However, binding to CD4 is not sufficient for infection, as
HIV gp120 also must bind to other cell surface molecules (coreceptors) for entry into the cell.
Chemokine receptors, particularly CCR5 and CXCR4, serve this role. HIV isolates can be
distinguished by their use of these coreceptors: R5 strains use CCR5, X4 strains use CXCR4, and
some strains (R5X4) are dual-tropic. R5 strains preferentially infect cells of the
monocyte/macrophage lineage and are thus referred to as M-tropic, whereas X4 strains are T-
tropic, preferentially infecting T cells, but these distinctions are not absolute. Polymorphisms in
the gene encoding CCR5 are associated with altered susceptibility to HIV infection.
Viral Replication: Once internalized, the RNA genome of the virus undergoes reverse
transcription, leading to the synthesis of double stranded complementary DNA (cDNA; proviral
DNA).In quiescent T cells, HIV cDNA may remain in the cytoplasm in a linear episomal form.
In dividing T cells, the cDNA circularizes, enters the nucleus, and is then integrated into the host
genome. After integration, the provirus may be silent for months or years, a form of latent
infection. The nucleus, NF-κB binds to regulatory sequences within several genes, including
genes for cytokines and other immune mediators, promoting their transcription. The long-
terminal-repeat sequences that flank the HIV genome also contain NF-κB–binding sites, so
binding of the transcription factor activates viral gene expression. Furthermore, TNF and other
cytokines produced by activated macrophages also stimulate NF-κB activity and thus lead to
production of HIV RNA. Thus, it seems that HIV thrives when the host T cells and macrophages
are physiologically activated, a situation that can be described as “subversion from within.” Such
activation in vivo may result from antigenic stimulation by HIV itself or by other infecting
microorganisms. HIV-positive individuals are at increased risk
Natural History and Course of HIV Infection
HIV disease begins with acute infection, which is only partly controlled by the host immune
response, and advances to chronic progressive infection of peripheral
lymphoid tissues • Acute phase. Virus typically enters through mucosal surfaces, and acute
(early) infection is characterized by infection of memory CD4+ T cells (which express CCR5) in
mucosal lymphoid tissues, and the death of many of these infected cells. Mucosal infection is
followed by dissemination of the virus and the development of host immune responses. DCs in
epithelia at sites of virus entry capture the virus and then migrate into the lymph nodes. Once in
lymphoid tissues, DCs pass HIV on to CD4+ T cells through direct cell–cell contact. Within days
after the first exposure to HIV, viral replication can be detected in lymph nodes. Within 3 to 6
weeks after initial infection, 40% to 90% of infected individuals develop an acute HIV
syndrome, which is triggered by the initial spread of the virus and the host response. This phase
is associated with a selflimited acute illness with nonspecific symptoms, including sore throat,
myalgias, fever, weight loss, and fatigue, resembling a flulike syndrome. Rash,
lymphadenopathy, diarrhea, and vomiting also may occur. This typically resolves spontaneously
in 2 to 4 weeks. As the infection spreads, the individual mounts antiviral humoral and cell-
mediated immune responses. These responses are evidenced by seroconversion (usually within 3
to 7 weeks of presumed exposure) and by the appearance of virus-specific CD8+ cytotoxic T
cells. HIV-specific CD8+ T cells are detected in the blood at about the time viral titers begin to
fall and are most likely responsible for the initial containment of HIV infection.
Clinical Features of AIDS
adult patient with AIDS presents with fever, weight loss, diarrhea, generalized
lymphadenopathy, multiple opportunistic infections, neurologic disease, and, in many cases,
secondary neoplasms.
Opportunistic Infections: Opportunistic infections account for the majority of deaths in untreated
patients with AIDS. Many of these infections represent reactivation of latent infections, which
are normally kept in check by a robust immune system but are not completely eradicated because
the infectious agents have evolved to coexist with their hosts. The actual frequency of infections
varies in different regions of the world Candidiasis is the most common fungal infection in
patients with AIDS, and infection of the oral cavity, vagina, and esophagus are its most common
clinical manifestations. • Cytomegalovirus (CMV) may cause disseminated disease, but more
commonly affects the eye and gastrointestinal tract. • Disseminated bacterial infection with
nontuberculous, or atypical, mycobacteria (mainly Mycobacterium aviumintracellulare) also
occurs late, in the setting of severe immunosuppression. Cryptococcosis occurs in about 10% of
AIDS patients. As in other settings with immunosuppression, meningitis is the major clinical
manifestation of cryptococcosis. • JC virus, a human papovavirus, is another important cause of
CNS infections in HIV-infected patients. It causes progressive multifocal leukoencephalopathy
Tumors Patients with AIDS have a high incidence of certain tumors, notably Kaposi sarcoma, B
cell lymphoma, cervical cancer in women, and anal cancer in men. Many of these tumors are
caused by oncogenic DNA viruses, including Kaposi sarcoma herpesvirus (Kaposi sarcoma),
EBV (B cell lymphoma), and human papillomavirus (cervical and anal carcinoma).
Nevertheless, HIV-infected individuals remain more susceptible to tumors that occur in the
general population, such as lung and skin cancers and certain forms of lymphoma.
Lymphomas: Lymphoma occurs at a markedly increased rate in individuals with AIDS, making
it another AIDSdefining tumor. . Even in the era of anti-retroviral therapy, lymphoma continues
to occur in HIV-infected individuals at an incidence that is at least 10-fold greater than the
population average. Based on molecular characterization of HIV-associated lymphomas and the
epidemiologic considerations above, at least two mechanisms appear to underlie the increased
risk for B-cell tumors in HIV-infected individuals. • Tumors Induced by Oncogenic Viruses. •
Germinal Center B-Cell Hyperplasia.
Central Nervous System Disease: Involvement of the CNS is a common and important
manifestation of AIDS. Ninety percent of patients demonstrate some form of neurologic
involvement at autopsy, and 40% to 60% have clinically apparent neurologic dysfunction.
Importantly, in some patients, neurologic manifestations may be the sole or earliest presenting
feature of HIV infection.
 References
robbins basic pathology-9tn ed
Microbiology - an introduction; 12th edition
Microbiology: a laboratory manual; 10th editio