2. Outline
▪ Immunodeficiency Syndromes
▪ Primary (Inherited) Immunodeficiencies
▪ Defects in Innate Immunity
▪ Secondary (Acquired) Immunodeficiencies
▪ Acquired Immunodeficiency Syndrome; Epidemiology; Properties of HIV ;
Pathogenesis of HIV Infection and AIDS; Natural History and Course of
HIV Infection; Clinical Features of AIDS
▪ Amyloidosis; Pathogenesis of Amyloid Deposition; Classification of
Amyloidosis and Mechanisms of Amyloid Formation
▪ References
3. Immunodeficiency Syndromes
▪ Divided into primary (or congenital) immunodeficiency disorders, which are
genetically determined.
▪ Secondary (or acquired) immunodeficiencies; may arise as complications of
cancers, infections, malnutrition, or side effects of immunosuppression,
irradiation, or chemotherapy for cancer and other diseases.
▪ Immunodeficiencies are manifested clinically by increased infections, which
may be newly acquired or reactivation of latent infections.
▪ The primary immunodeficiency syndromes are accidents of nature that provide
valuable insights into some of the molecules critical in the development of the
immune system.
▪ Several immunodeficiencies also are associated with autoimmune disorders,
perhaps the deficiency results in loss of regulatory mechanisms or persistence
of infections that promote autoimmunity.
4. Primary (Inherited) Immunodeficiencies
▪ 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.
5.
6. 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.
7. Severe Combined Immunodeficiency Disease
▪ The defect resides in the T-cell compartment, with a secondary
impairment of humoral immunity.
▪ 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.
▪ 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
8. ▪ Currently, HSC transplantation is the mainstay of treatment.
▪ X-linked SCID is the first disease in which gene therapy has been
successful.
Severe Combined Immunodeficiency Disease
9. X-Linked Agammaglobulinemia
▪ Bruton disease is characterized by the failure of pre–B cells to
differentiate into mature B cells and, as the name implies, a resultant
absence of antibodies (gamma globulin) in the blood.
▪ It is one of the more common forms of primary immunodeficiency,
occurring at a frequency of about 1 in 100,000 male infants.
▪ During normal B-cell maturation, immunoglobulin (Ig) heavy chain genes
are rearranged first, followed by light chain genes.
▪ At each stage, signals are received from the expressed components of
the antigen receptor that drive maturation to the next stage.
▪ These signals act as quality controls, to ensure that the correct receptor
proteins are being produced.
10. ▪ Classically, the disease is characterized by a profound reduction in the
number of B cells in the blood and secondary lymphoid organs and an
absence of germinal centers and plasma cells in these organs.
▪ T-cell numbers and responses may be normal.
▪ The disease usually does not become apparent until about 6 months of
age, as maternal antibodies that were transported via the placenta are
depleted.
▪ Recurrent bacterial infections of the respiratory tract; call attention to the
underlying immune defect.
▪ Almost always, the causative organisms are Haemophilus influenzae,
Streptococcus pneumoniae, or Staphylococcus aureus, organisms that
are normally opsonized by antibodies and cleared by phagocytosis.
X-Linked Agammaglobulinemia
11. ▪ Immunization with live poliovirus carries the risk for paralytic
poliomyelitis, and infections with echovirus can cause fatal encephalitis.
▪ Giardia lamblia, an intestinal protozoan that is normally resisted by
secreted IgA, causes persistent infections in individuals with this disorder.
▪ Many intracellular viral, fungal, and protozoal infections are handled quite
well by the intact T cell–mediated immunity.
▪ For unclear reasons, autoimmune diseases (such as rheumatoid arthritis
and dermatomyositis) occur in as many as 35% of patients with this
disease.
▪ The treatment is replacement therapy with intravenous immunoglobulin
(IVIG) from pooled human serum.
X-Linked Agammaglobulinemia
12. DiGeorge Syndrome (Thymic Hypoplasia)
▪ Caused by a congenital defect in thymic development resulting in deficient T-cell
maturation.
▪ T cells are absent in the lymph nodes, spleen, and peripheral blood, and infants
with this defect are extremely vulnerable to viral, fungal, and protozoal
infections.
▪ Patients also are susceptible to infection with intracellular bacteria, because of
defective T cell–mediated immunity.
▪ B cells and serum immunoglobulins are generally unaffected.
▪ The thymic and T-cell defects, there may be parathyroid gland hypoplasia,
resulting in hypocalcemic tetany, as well as additional midline developmental
abnormalities.
▪ Transplantation of thymic tissue has successfully treated some affected infants.
▪ In patients with partial defects, immunity may improve spontaneously with age.
13. Hyper-IgM Syndrome
▪ Characterized by the production of normal (or even supra-normal) levels of IgM
antibodies and decreased levels of the IgG, IgA, and IgE isotypes; the underlying
defect is an inability of T cells to activate B cells.
▪ Many of the functions of CD4+ helper T cells require the engagement of CD40
on B cells, macrophages, and dendritic cells by CD40L expressed on antigen-
activated T cells.
▪ This interaction triggers Ig class switching and affinity maturation in the B cells,
and stimulates the microbicidal functions of macrophages.
▪ Approximately 70% of individuals with hyper-IgM syndrome have the X-linked
form of the disease, caused by mutations in the gene encoding CD40L.
14. Hyper-IgM Syndrome
▪ In 30% of patients; the disease is inherited in an autosomal recessive pattern
caused by loss of function mutations involving either CD40 or an enzyme called
activation-induced cytidine deaminase (AID); a DNA-editing enzyme that is
required for Ig class switching and affinity maturation
▪ Patients present with recurrent pyogenic infections because of low levels of
opsonizing IgG antibodies.
▪ Those with CD40L mutations also are susceptible to pneumonia caused by the
intracellular organism Pneumocystis jiroveci, because CD40L-mediated
macrophage activation is compromised.
▪ IgM antibodies react with blood cells, giving rise to autoimmune hemolytic
anemia, thrombocytopenia, and neutropenia.
▪ In older patients, there may be a proliferation of IgM-producing plasma cells that
infiltrate the mucosa of the gastrointestinal tract
15. Isolated IgA Deficiency
▪ This is the most common primary immune deficiency disease, affecting
about 1 in 700 whites.
▪ IgA is the major immunoglobulin in mucosal secretions and is thus involved
in defending the airways and the gastrointestinal tract.
▪ Weakened mucosal defenses due to IgA deficiency predispose patients to
recurrent sinopulmonary infections and diarrhea.
▪ There also is a significant (but unexplained) association with autoimmune
diseases.
▪ The pathogenesis of IgA deficiency seems to involve a block in the terminal
differentiation of IgA-secreting B cells to plasma cells; IgM and IgG
subclasses of antibodies are present in normal or even supranormal levels.
▪ The molecular basis for this defect is not understood.
16. Wiskott-Aldrich syndrome
▪ An X-linked disease characterized by thrombocytopenia, eczema, and a marked
vulnerability to recurrent infection that results in early death.
▪ The thymus is normal, at least early in the disease course, but there is progressive
loss of T lymphocytes from the blood and the T cell zones (paracortical areas) of
lymph nodes, with variable defects in cellular immunity.
▪ Patients do not make antibodies to polysaccharide antigens, and the response to
protein antigens is poor.
▪ IgM levels in the serum are low, but levels of IgG are usually normal and,
paradoxically, IgA and IgE are often elevated.
▪ Mutations in an X-linked gene encoding Wiskott-Aldrich syndrome protein (WASP).
▪ WASP belongs to a family of signaling proteins that link membrane receptors, such
as antigen receptors, to cytoskeletal elements.
17. Wiskott-Aldrich Syndrome
▪ The WASP protein is involved in cytoskeleton-dependent responses,
including cell migration and signal transduction, but how this
contributes to the functions of lymphocytes and platelets is unclear.
▪ The only treatment is HSC transplantation.
18. Defects in Innate Immunity
▪ Inherited defects in the early innate immune response typically affect
leukocyte functions or the complement system and lead to increased
vulnerability to infections.
▪ Defects in Leukocyte Function
▪ Leukocyte adhesion deficiencies (LADs) stem from inherited defects in
adhesion molecules that impair leukocyte recruitment to sites of infection,
resulting in recurrent bacterial infections.
▪ LAD1 is caused by defects in the β2 chain that is shared by the integrins
LFA-1 and Mac-1.
▪ LAD2 is caused by a defect in a fucosyl transferase that is required to
synthesize functional sialyl-Lewis X, the ligand for E- and P-selectins.
19. Defects in Innate Immunity
▪ Chronic granulomatous disease results from inherited defects in the genes
encoding components of phagocyte oxidase.
▪ The phagolysosomal enzyme that generates ROS such as superoxide resulting
in defective bacterial killing and susceptibility to recurrent bacterial infection.
▪ The name of this disease comes from the macrophage-rich chronic
inflammatory reaction that appears at sites of infection if the initial neutrophil
defense is inadequate.
▪ These collections of activated macrophages form granulomas in an effort to
wall off the microbes.
20. Defects in Innate Immunity
▪ Chédiak-Higashi syndrome is characterized by defective fusion of
phagosomes and lysosomes, resulting in defective phagocyte function and
susceptibility to infections.
▪ The main leukocyte abnormalities are neutropenia, defective degranulation,
and delayed microbial killing.
▪ The affected leukocytes contain giant granules, which are readily seen in
peripheral blood smears and are thought to result from aberrant
phagolysosome fusion.
▪ There are abnormalities in melanocytes (leading to albinism), cells of the
nervous system (associated with nerve defects), and platelets (causing
bleeding disorders).
▪ The gene associated with this disorder encodes a large cytosolic protein
called LYST, which is believed to regulate lysosomal trafficking.
21.
22. Deficiencies Affecting the Complement System
▪ C2 deficiency being the most common.
▪ Deficiencies of C2 or C4, early components of the classical pathway, are associated
with increased bacterial or viral infections; many patients are asymptomatic,
presumably because the alternative complement pathway is able to control most
infections.
▪ In some patients with C2, C4, or C1q deficiency, the dominant manifestation is an SLE-
like autoimmune disease, possibly because these factors are involved in clearance of
immune complexes.
▪ Deficiency of C3 is rare; It is associated with severe pyogenic infections as well as
immune complex–mediated glomerulonephritis.
▪ Deficiency of the late components C5 to C9 results in increased susceptibility to
recurrent neisserial (gonococcal and meningococcal) infections, as Neisseria bacteria
have thin cell walls and are especially susceptible to the lytic actions of complement.
23. Deficiencies Affecting the Complement System
▪ Defects in complement regulatory proteins result in excessive inflammation or
cell injury.
▪ A deficiency of C1 inhibitor (C1 INH) gives rise to an autosomal dominant
disorder called hereditary angioedema.
▪ C1 INH is an inhibitor of many proteases, including kallikrein and coagulation
factor XII, both of which are involved in the production of vasoactive peptides
such as bradykinin.
▪ Defective C1 INH activity leads to over-production of bradykinin, which is a
potent vasodilator.
▪ Affected patients have episodes of edema affecting skin and mucosal
surfaces such as the larynx and the gastrointestinal tract.
24. Deficiencies Affecting the Complement System
▪ Acquired deficiencies of other complement regulatory proteins are
the cause of paroxysmal nocturnal hemoglobinuria
▪ Some cases of hemolytic uremic syndrome stem from inherited
defects in complement regulatory proteins.
25.
26.
27. Secondary/ Acquired Immunodeficiency
▪ May be encountered in individuals with cancer, diabetes and other
metabolic diseases, malnutrition, chronic infection, and
▪ In patients receiving chemotherapy or radiation therapy, or
▪ Immunosuppressive drugs to prevent graft rejection or to treat
autoimmune diseases.
▪ The secondary immune deficiencies are more common than the
disorders of primary genetic origin.
28.
29. Acquired Immunodeficiency Syndrome
▪ 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.
▪ First recognized as a distinct entity as recently as the 1980s.
▪ Of the estimated 36 million HIV-infected individuals worldwide, about 70%
are in Africa and 20% in Asia.
▪ More than 25 million deaths are attributable to HIV/AIDS, with 1 to 2 million
deaths annually.
▪ Effective anti-retroviral drugs have been developed, but the infection
continues to spread in parts of the world where these therapies are not
widely available.
▪ In some African countries, more than 30% of the population is HIV infected
30. Acquired Immunodeficiency Syndrome
▪ Despite the remarkable progress in drug therapy of AIDS, cure is still a
distant goal.
▪ The advent of these drugs also raises its own tragic concern; more
individuals are living with HIV, the risk of spreading the infection will
increase if vigilance is relaxed.
31. Epidemiology
▪ Epidemiologic studies in the United States have identified five groups of adults at high
risk for developing AIDS.
▪ Homosexual or bisexual men constitute the largest group, accounting for about 50% of
the reported cases; includes about 5% who also are intravenous drug abusers.
▪ Heterosexual contacts of members of other high-risk groups constituted about 20% of
infections from 2001 to 2004; In Africa and Asia, this is by far the largest group of
patients with new infections, most of which occur in women who are infected by male
partners.
▪ Intravenous drug abusers with no previous history of homosexuality represented about
20% of infected individuals and 9% of new cases in 2009.
▪ Surviving hemophiliacs, especially those who received large amounts of factor VIII or
factor IX concentrates before 1985, make up about 0.5% of all cases.
▪ Other recipients of HIV-infected whole blood or components (e.g., platelets, plasma)
account for about 1% of patients.
32. Epidemiology
▪ HIV infection of the newborn. Close to 2% of all AIDS cases occur in this
pediatric population; The vast majority acquires the infection by transmission
of the virus from mother to child.
▪ In approximately 5% of cases, the risk factors cannot be determined.
▪ Transmission of HIV occurs under conditions that facilitate exchange of blood
or body fluids containing the virus or virus-infected cells:
▪ Sexual Transmission; Dominant mode; more than 75% of the cases
▪ Parenteral Transmission; IV Drug Abusers, Hemophiliacs.
▪ Mother-to-Infant Transmission; Major cause of Pediatric AIDS; (1) in utero by
transplacental spread; (2) during delivery through an infected birth canal; and
(3) after birth by ingestion of breast milk
33. Epidemiology
▪ Transmission during birth (intrapartum) and in the immediate period
thereafter (peripartum) is considered to be the most common mode in the
United States.
▪ The reported transmission rates vary from 7% to 49% in different parts of the
world.
▪ Higher risk of transmission is associated with high maternal viral load and
low CD4+ T cell counts as well as chorioamnionitis.
▪ After needle-stick accidents, the risk for seroconversion is believed to be
about 0.3%, and antiretroviral therapy given within 24 to 48 hours of a
needle stick can greatly reduce the risk of infection.
▪ Approximately 30% of those accidentally exposed to hepatitis B–infected
blood become seropositive.
34. Properties of Human Immunodeficiency Virus
▪ Non-transforming human retrovirus belonging to the lentivirus family.
▪ Feline immunodeficiency virus, simian immunodeficiency virus, visna virus of
sheep, bovine immunodeficiency virus, and the equine infectious anemia
virus.
▪ HIV-1 is the most common type associated with AIDS in the United States,
Europe, and Central Africa.
▪ HIV-2 causes a similar disease principally in West Africa and India.
▪ 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) nucleo-capsid
protein p7/p9; (3) two copies of viral genomic RNA; and (4) the three viral
enzymes (protease, reverse transcriptase, and integrase).
35.
36. Pathogenesis of HIV Infection and AIDS
▪ The two major targets of HIV infection are the immune system and the
central nervous system.
▪ Profound immune deficiency, primarily affecting cell-mediated immunity,
is the hallmark of AIDS.
▪ This results chiefly from infection and subsequent loss of CD4+ T cells as
well as impaired function of surviving helper T cells and other immune
cells.
▪ 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.
▪ HIV infects cells by using the CD4 molecule as a receptor and various
chemokine receptors as co-receptors
37. Pathogenesis of HIV Infection and AIDS
▪ 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.
▪ Proviral DNA may be transcribed, leading to the expression of viral proteins that are
required for the formation of complete viral particles.
▪ HIV infects memory cells and activated T cells but is inefficient at productively infecting
naïve (resting) T cells.
▪ Completion of the viral life cycle in latently infected cells occurs only after cell activation,
and in the case of most CD4+ T cells, virus activation results in death of the infected
cells
38. Pathogenesis of HIV Infection and AIDS
▪ Loss of CD4+ T cells is mainly caused by the direct cytopathic effects of the
replicating virus.
▪ In infected individuals, approximately 100 billion new viral particles are
produced and 1 to 2 billion CD4+ T cells die each day.
▪ Death of these cells is a major cause of the relentless, and eventually
profound, T cell immunodeficiency.
▪ The immune system can replace the dying T cells, but as the disease
progresses, renewal of CD4+ T cells cannot keep up with their loss.
▪ Direct Killing of Immune Cells and other mechanisms
39. Pathogenesis of HIV Infection and AIDS
▪ Chronic activation of uninfected cells, responding to HIV itself or to infections
that are common in individuals with AIDS, leading to apoptosis of these cells.
▪ HIV infection of cells in lymphoid organs (spleen, lymph nodes, tonsils) causing
progressive destruction of the architecture and cellular composition of
lymphoid tissues.
▪ Fusion of infected and uninfected cells, leading to formation of syncytia (giant
cells); Fused cells usually die within a few hours.
▪ Qualitative defects in T cell function; reduction in antigen-induced T cell
proliferation, a decrease in TH1-type responses relative to the TH2 type, defects
in intracellular signaling, and many more.
▪ Low-level chronic or latent infection of T cells is an important feature of HIV
infection.
40. Pathogenesis of HIV and AIDS
▪ Macrophages. Similar to T cells, most macrophages infected by HIV are found
in tissues, and in certain tissues, such as the lungs and brain, as many as
10% to 50% of macrophages are infected.
▪ Dendritic Cells. Mucosal DCs may be infected by the virus and transport it to
regional lymph nodes, where the virus is transmitted to CD4+ T cells.
▪ B Cell Function in HIV Infection. Although B cells cannot be infected by HIV,
they may show profound abnormalities.
▪ Paradoxically, there is spontaneous B-cell activation and
hypergammaglobulinemia in association with an inability to mount antibody
responses to newly encountered antigens
41.
42.
43. Course of HIV Infection
▪ Acute phase. Virus typically enters through mucosal surfaces, and acute (early)
infection is characterized by infection of memory CD4+ T cells in mucosal
lymphoid tissues, and the death of many of these infected cells.
▪ The mucosal tissues are the largest reservoir of T cells in the body and a major
site of residence of memory T cells, this local loss results in considerable
depletion of lymphocytes.
▪ At this stage, few infected cells are detectable in the blood and other tissues.
▪ Mucosal infection is followed by dissemination of the virus and the
development of host immune responses.
▪ Within 3 to 6 weeks after initial infection, 40% to 90% of infected individuals
develop an acute HIV syndrome.
44. Course of HIV Infection
▪ Triggered by the initial spread of the virus and the host response.
▪ This phase is associated with a self-limited 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.
▪ 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.
45. Course of HIV Infection
▪ Chronic phase. In the next, chronic phase of the disease, lymph
nodes and the spleen are sites of continuous HIV replication and
cell destruction.
▪ During this period of the disease, few or no clinical manifestations
of the HIV infection are present; clinical latency period.
▪ Although few peripheral blood T cells harbor the virus, destruction
of CD4+ T cells within lymphoid tissues (up to 10% of which may
be infected) continues during this phase, and the number of
circulating blood CD4+ T cells steadily declines
46. Course of HIV Infection
▪ AIDS. The final phase is progression to AIDS, characterized by a breakdown of
host defense, a dramatic increase in plasma virus, and severe, life-
threatening clinical disease.
▪ Typically the patient presents with long-lasting fever (>1 month), fatigue,
weight loss, and diarrhea.
▪ After a variable period, serious opportunistic infections, secondary
neoplasms, or clinical neurologic disease (grouped under the rubric AIDS
indicator diseases or AIDS-defining illnesses, discussed later) emerge, and the
patient is said to have developed AIDS.
▪ The extent of viremia, measured as HIV-1 RNA levels in the blood, is a useful
marker of HIV disease progression and is of value in the management of HIV-
infected individuals.
47. Course of HIV Infection
▪ Centers for Disease Control and Prevention (CDC) classification of HIV infection
stratifies patients into three groups based on CD4+ cell counts:
▪ Greater than or equal to 500 cells/μL, 200 to 499 cells/μL, and fewer than 200
cells/μL
▪ In the absence of treatment, most patients with HIV infection progress to AIDS after
a chronic phase lasting from 7 to 10 years, but there are exceptions.
▪ In rapid progressors, the middle, chronic phase is telescoped to 2 to 3 years after
primary infection.
▪ About 5% to 15% of infected individuals are long-term nonprogressors, defined as
untreated HIV-1–infected individuals who remain asymptomatic for 10 years or
more, with stable CD4+ T cell counts and low levels of plasma viremia (usually <500
viral RNA copies/ mL).
▪ Remarkably, about 1% of infected individuals have undetectable plasma virus (<50
to 75 RNA copies/mL); these have been called elite controllers
48.
49.
50.
51. Clinical Features of AIDS
▪ Opportunistic Infections; Pneumonia (15-30%),Candidosis, CMV
▪ Highly Active Anti-Retroviral Therapy (HAART)
▪ Tumors; notably Kaposi sarcoma, B cell lymphoma, cervical cancer in
women, and anal cancer in men; considered AIDS-defining malignancies;
estimated that 25% to 40% of untreated HIV-infected individuals will
eventually develop a malignancy.
▪ Central Nervous System Disease; 40-60%
52. Amyloidosis
▪ A condition associated with a number of disorders in which extracellular
deposits of fibrillar proteins are responsible for tissue damage and functional
compromise.
▪ These abnormal fibrils are produced by the aggregation of improperly folded
proteins (which are soluble in their normal folded configuration).
▪ The fibrillar deposits bind a wide variety of proteoglycans and
glycosaminoglycans, which contain charged sugar groups that give the
deposits staining characteristics thought to resemble those of starch
(amylose).
▪ The deposits were called amyloid.
▪ At least 30 different proteins can aggregate to form fibrils with the
appearance of amyloid.
53. Amyloidosis
▪ All amyloid deposits are composed of non-branching fibrils, each formed of
intertwined polypeptides in a β pleated sheet conformation.
▪ Approximately 95% of the amyloid material consists of fibril proteins, the
remaining 5% being various glycoproteins.
▪ The three most common forms of amyloid are:
▪ AL (amyloid light chain) amyloid is made up of complete immunoglobulin light
chains, the amino-terminal fragments of light chains, or both.
▪ AA (amyloid-associated) amyloid is composed of an 8500- dalton protein derived
by proteolysis from a larger precursor in the blood called SAA (serum amyloid-
associated) protein, which is synthesized in the liver.
▪ β-amyloid protein (Aβ) is a 4000-dalton peptide that is derived by proteolysis
from a much larger transmembrane glycoprotein, called amyloid precursor
protein.
54. Amyloidosis
▪ Amyloidosis results from abnormal folding of proteins, which assume a β pleated
sheet conformation, aggregate, and deposit as fibrils in extracellular tissues.
▪ The proteins that form amyloid fall into two general categories:
1. Normal proteins that have an inherent tendency to associate and form fibrils,
particularly when produced in increased amounts
2. Mutant proteins that are prone to misfolding and aggregation.
▪ Amyloid may be systemic; subclassified into primary amyloidosis [associated with
a clonal plasma cell proliferation], or secondary [complication of an underlying
chronic inflammatory or tissue-destructive process.]
▪ Localized to a single organ, such as the heart.
▪ Hereditary or familial amyloidosis; heterogeneous group with several distinctive
patterns of organ involvement
55.
56.
57. Primary Amyloidosis: Plasma Cell Proliferations
Associated With Amyloidosis
▪ Amyloid in this category is of the AL type and is usually systemic in distribution.
▪ This is the most common form of amyloidosis, with approximately 2000 to
3000 new cases each year in the United States.
▪ It is caused by a clonal proliferation of plasma cells that synthesize abnormal
Ig molecules.
▪ The AL type of systemic amyloidosis occurs in 5% to 15% of individuals with
multiple myeloma, a plasma-cell tumor characterized by excessive production
of free immunoglobulin light Chains.
▪ The free, unpaired κ or λ light chains (Bence Jones protein) are prone to
aggregating and depositing in tissues as amyloid.
58. Reactive Systemic Amyloidosis
▪ The amyloid deposits in this pattern are systemic in distribution and are
composed of AA protein.
▪ Previously referred to as secondary amyloidosis because it is secondary to an
associated inflammatory condition.
▪ Tuberculosis, bronchiectasis, and chronic osteomyelitis were the most
important underlying conditions.
▪ Currently, these conditions frequently resolve with antibiotic treatment and less
often lead to amyloidosis.
▪ Reactive Systemic amyloidosis complicates rheumatoid arthritis (3%), other
connective tissue disorders such as ankylosing spondylitis, and inflammatory
bowel disease.
59.
60. Heredofamilial Amyloidosis
▪ A variety of familial forms of amyloidosis have been described. Most are rare and
occur in limited geographic areas.
▪ The most common and best studied is an autosomal recessive condition called
familial Mediterranean fever, which is encountered largely in individuals of
Armenian, Sephardic Jewish, and Arabic origins.
▪ Auto-inflammatory” syndrome associated with excessive production of the
cytokine IL-1 in response to inflammatory stimuli.
▪ Characterized by attacks of fever accompanied by inflammation of serosal
surfaces that manifests as peritonitis, pleuritis, and synovitis.
▪ The gene for familial Mediterranean fever encodes a protein called pyrin that is
important in dampening the response of innate immune cells, particularly
neutrophils, to inflammatory mediators.
61. ▪ The amyloid seen in this disorder is of the AA type, suggesting that it is related
to the recurrent bouts of inflammation.
▪ In contrast to familial Mediterranean fever, a group of autosomal dominant
familial disorders is characterized by deposition of amyloid made up of fibrils
derived from mutant transthyretin (TTR) [4% of Black Population.]
Heredofamilial Amyloidosis
62. Hemodialysis-Associated Amyloidosis
▪ Long-term hemodialysis for renal failure can develop amyloid deposits derived
from β2-microglobulin.
▪ This protein is present in high concentrations in the serum of individuals with
renal disease, and in the past it was retained in the circulation because it could
not be filtered through dialysis membranes.
▪ With new dialysis filters, theincidence of this complication has decreased
substantially.
▪ The classical features of this form of amyloidosis are the triad of scapulohumeral
periarthritis, carpal tunnel syndrome, and flexor tenosynovitis of the hand.
63. Localized Amyloidosis
▪ Amyloid deposits are limited to a single organ or tissue without involvement
of any other site in the body.
▪ The deposits may produce grossly detectable nodular masses or be evident
only on microscopic examination.
▪ Nodular deposits of amyloid are most often encountered in the lung, larynx,
skin, urinary bladder, tongue, and the region about the eye.
▪ Frequently, there are infiltrates of lymphocytes and plasma cells associated
with these amyloid masses.
▪ The amyloid consists of AL protein and may therefore represent a localized
form of plasma cell–derived amyloid.
64. Endocrine Amyloid
▪ Microscopic deposits of localized amyloid may be found in certain endocrine
tumors, such as medullary carcinoma of the thyroid gland, islet tumors of the
pancreas, pheochromocytomas and undifferentiated carcinomas of the
stomach,
▪ In the islets of Langerhans in individuals with type 2 diabetes mellitus.
▪ The amyloidogenic proteins seem to be derived either from polypeptide
hormones (e.g., medullary carcinoma) or from unique proteins (e.g., islet
amyloid polypeptide).
65. Amyloid of Aging
▪ Several well-documented forms of amyloid deposition occur with aging.
▪ Senile systemic amyloidosis refers to the systemic deposition of amyloid in
elderly patients (usually in their seventies and eighties).
▪ Because of the dominant involvement and related dysfunction of the heart, this
form was previously called senile cardiac amyloidosis.
▪ Those who are symptomatic present with a restrictive cardiomyopathy and
arrhythmias
▪ The amyloid in this form, in contrast to familial forms, is derived from normal
TTR.
66.
67. Clinical Features
▪ May be found as an unsuspected anatomic change, having produced no clinical
manifestations
▪ May cause serious clinical problems and even death.
▪ The symptoms depend on the magnitude of the deposits and on the sites or
organs affected.
▪ Clinical manifestations at first are often entirely nonspecific, such as weakness,
weight loss, lightheadedness, or syncope.
▪ More specific findings appear later and most often relate to renal, cardiac, and
gastrointestinal involvement.
▪ Renal involvement gives rise to proteinuria that may be severe enough to cause
the nephrotic syndrome
68. Clinical Features
▪ Progressive obliteration of glomeruli in advanced cases ultimately leads to
renal failure and uremia.
▪ Renal failure is a common cause of death.
▪ Cardiac amyloidosis may present insidiously as congestive heart failure.
▪ The most serious aspects of cardiac amyloidosis are conduction disturbances
and arrhythmias, which may prove fatal.
▪ Occasionally, cardiac amyloidosis produces a restrictive pattern of
cardiomyopathy and masquerades as chronic constrictive pericarditis.
▪ Gastrointestinal amyloidosis may be asymptomatic.
▪ Amyloidosis of the tongue may cause sufficient enlargement and inelasticity to
hamper speech and swallowing.
69. Clinical Features
▪ Depositions in the stomach and intestine may lead to
malabsorption, diarrhea, and disturbances in digestion.
▪ Vascular amyloidosis causes vascular fragility that may lead to
bleeding, sometimes massive, that can occur spontaneously or
following seemingly trivial trauma.
▪ In some cases AL amyloid binds and inactivates factor X, a critical
coagulation factor, leading to a life-threatening bleeding disorder.
70. Diagnosis
▪ The diagnosis of amyloidosis depends on the histologic demonstration of amyloid
deposits in tissues.
▪ The most common sites biopsied are the kidney, when renal manifestations are present,
or rectal or gingival tissues in patients suspected of having systemic amyloidosis.
▪ Examination of abdominal fat aspirates stained with Congo red can also be used for the
diagnosis of systemic amyloidosis.
▪ The test is quite specific, but its sensitivity is low.
▪ In suspected cases of AL amyloidosis, serum and urine protein electrophoresis and
immunoelectrophoresis should be performed.
▪ Bone marrow aspirates in such cases often show a monoclonal population of plasma
cells, even in the absence of overt multiple myeloma.
▪ Scintigraphy with radiolabeled serum amyloid P (SAP) component is a rapid and specific
test, since SAP binds to the amyloid deposits and reveals their presence.
71. Prognosis
▪ The prognosis for individuals with generalized amyloidosis is poor.
▪ Those with AL amyloidosis (not including multiple myeloma) have a median
survival of 2 years after diagnosis.
▪ Individuals with myeloma-associated amyloidosis have an even poorer
prognosis.
▪ The outlook for individuals with reactive systemic amyloidosis is somewhat
better and depends to some extent on the control of the underlying condition.
▪ Resorption of amyloid after treatment of the associated condition has been
reported, but this is a rare occurrence.
▪ New therapeutic strategies aimed at correcting protein misfolding and
inhibiting fibrillogenesis are being developed.
