Acquired Immunodeficiencies Secondary or Acquired Immunodeficiencies Agentinduced immunodeficiency eg infections including HIV Metabolic disorders and trauma Splenectomy Drugs such as corticosteroids cyclosporin A radiation and chemotherapy ID: 927876
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Slide1
Secondary immunodeficiency
(Acquired Immunodeficiencies)
Slide2Secondary or Acquired Immunodeficiencies
Agent-induced immunodeficiency: e.g. infections including HIV
Metabolic disorders and trauma
Splenectomy
Drugs such as corticosteroids, cyclosporin A, radiation and chemotherapy
Aging
Slide3Human Immunodeficiency Virus
Discovered in 1983
by Luc Montagnier (Lymphadenopathy virus; Nobel Prize) and Robert Gallo (HTLV-III)
Is a member of
genus retrovirus (RNA virus)
belonging to Lentiviridae
Characterized by
long incubation period and slow course of disease
HIV-1
(Common in US) and
HIV-2
(in Africa)
AIDS patients have
low CD4
+
T cells
Virus prevalent in
homosexual
, promiscuous heterosexual,
i.v. drug users
, transfusion,
infants born to infected mothers
(prenatally, during birth and lactation)
Opportunistic infections
with
Candida albicans
,
Pnuemocystis carinii, Mycobacterium avium, Toxoplasma
, Cytomegalovirus (CMV), etc.
Patients with HIV
have high incidence of cancers
such as
Kaposi sarcoma and lymphomas
Slide4Viruses that cause infections, called R5 viruses, usually use CCR5 coreceptor, found on effector memory T cells, macrophages, and dendritic cells common in mucosal epithelia. These R5 viruses are the major virus type through much of
early infection period.
As the infection progresses, R5 viruses may mutate to preferring the CXCR4 coreceptor, enabling them to infect naïve as well as central memory T cell. These X4 viruses contribute to the
later significant decline in numbers of CD4
+
T cells.
CXCR4 and CCR5 serve as coreceptors for HIV infection of different cell types
Macrophages, DCs and effector memory T cells
Naïve and central memory T cells
R5 virus (M-Tropic)
X4 virus (T-Tropic)
Slide6Certain chemokines, such as RANTES, had a negative effect on virus replication. CCR5 and CXCR4 cannot bind simultaneously to HIV-1 and to their natural chemokine ligands. Competition for the receptor between the virus and the natural chemokine ligand can thus block viral entry into the host cell.
Individuals with deletion mutation in CCR5 gene making them resistant to viral variants that require this coreceptors.
Slide7Patients with AIDS generally die from tuberculosis, pneumonia, severe wasting diarrhea, or various malignancies. The time between acquisition of the virus and death from the immunodeficiency averages
nine to twelve years
.
A rise in the level of circulating HIV-1 (viral load) in the plasma and
concomitant drop
in the number of CD4 T cells generally previews this first appearance of symptoms.
Slide8E
vidence for infection with HIV-1 (presence of antibodies or virus in blood), greatly diminished numbers of CD4- T cells (200 cells/mm3), impaired or absent delayed-hypersensitivity reactions, and the occurrence of opportunistic infections.
Slide9Oral Candidiasis (Thrush)
Slide10Kaposi Sarcoma
Slide11Pathogenesis of HIV Infection and AIDS
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 .
The virus typically enters through mucosal epithelia. The subsequent events in the infection can be divided into several phases.
Slide12Acute (early) infection is characterized by infection of memory CD4+ T cells in mucosal lymphoid tissues and death of many infected cells.
The transition from the acute phase to the chronic phase of infection is accompanied by dissemination of the virus, viremia, and the development of host immune responses.
Slide13During the acute phase, HIV infection is spreading rapidly among CCR5- expressing T cells, and the
viral load
in the blood as well as in other body fluids can be quite high, elevating the risk of infecting others.
Dendritic cells in epithelia at sites of virus entry capture the virus and then migrate into the lymph nodes.
And may pass HIV on to CD4+ T cells through direct cell-cell contact.
Slide14Within days after the first exposure to HIV, viral replication can be detected in the lymph nodes. This replication
leads to viremia
, during which large numbers of HIV particles are present in the
patient’s blood
, accompanied by an acute HIV syndrome that includes a variety of nonspecific signs and symptoms typical of many viral infections
The
viremia
allows the virus to
disseminate throughout
the body and to infect CCR5 helper T cells, macrophages, and dendritic cells in peripheral lymphoid tissues.
Adaptive immune system mounts both humoral and cell-mediated immune responses directed at viral antigens control the infection and viral production,
and such control is reflected by a drop in viremia to low but detectable levels by approximately 12 weeks after the primary exposure.
Slide15The initial appearance of Ab against HIV Ag
seroconversion
usually occurs 1 to 3 months after infection.
The most commonly used test for HIV-specific Ab is an ELISA to detect the presence of Ab directed against HIV proteins.
Because of the delay in seroconversion, some HIV ELISA tests also look for HIV Ag in the blood, which may be detectable 2 to 6 weeks after infection.
Positive ELISA results are confirmed using either the more specific Western blot technique, which detect the presence of Ab against several HIV proteins, or PCR assays for HIV RNA.
Slide16Soon after infection, viral RNA is detectable in the serum. However, HIV infection is most commonly detected by the presence of anti-HIV antibodies after seroconversion, which normally occurs within two months of infection.
The
viral set point
refers to the level of virus in the blood at the time of rebound, when the immune response begins to control virus levels.
Clinical symptoms indicative of AIDS generally do not appear for 1 to 20 years after infection, but this interval is variable, and extended by antiretroviral therapy is used.
The onset of clinical AIDS is usually signaled by a decrease in T-cell numbers to below 200/ ml and a sharp increase in viral load.
Patients become very susceptible to opportunistic infections and other health problems.
Slide17viral set point
Slide18This stage is followed by an asymptomatic period during which there is a gradual decline in CD4+ T cells but usually no outward symptoms of disease.
This is driven by an immune response involving both antibody and cytotoxic CD8+ T lymphocytes that keeps viral replication in check and drives down the viral load.
Ab provide protection through neutralization, opsonization of virus, and binding to
gp
120 on the surface of infected cells, leading to their elimination by ADCC and phagocytosis.
Ab loses effectiveness as the virus mutates due to unrepaired replication errors made by reverse transcriptase.
Slide19The length of this asymptomatic window varies greatly and is likely due to a combination of host and viral factors.
viral replication continues, CD4+cell levels gradually fall, and viral load in the circulation can be measured by PCR assays for viral RNA. These measurements of viral load have assumed a major role in the determination of the patient’s status and prognosis.
Even when the level of virus in the circulation is stable, large amounts of virus are produced in infected CD4+ T cells; as many as 10
9
virions are released every day and continually infect and destroy additional host T cells.
Slide20During this time HIV is mutating, and viruses whose antigens changes to escape recognition by CTLs will survive.
The rapidly evolving virus presents challenges both for the immune system to keep up with these virus escape variants and for the development of drugs and vaccines to treat or prevent progression of the disease.
Slide21a dramatic depletion of lymphoid tissue and specifically CD4+ T cells from the GI tract during HIV infection, starting as early as the acute stages of infection.
The association between the GI tract and HIV
suggeste
that TH17 cells, which express both the CCR5 and CXCR4 coreceptors, are the primary targets of infection and destruction. These TH17 cells are thought to play an important role in homeostatic regulation of the innate and adaptive responses to microbial flora in the gut.
Destruction of these cells and disruption of the integrity of the mucosal barrier in the GI tract may allow for the translocation of microbial products across the epithelial lining, explaining some of the rampant immune stimulation that is characteristic of HIV infection.
In a deadly feedback loop, this immune stimulation generates yet more activated CD4+ cells, the favored targets for HIV infection and replication.
Slide22The severe decrease in CD4+ T cells is a clinical hallmark of AIDS
Several explanations have been advanced for the death of
uninfected
as well as
infected
CD4+Tcells.
Lysis of cells actively replicating HIV, abortive HIV infection of resting
Tcells
(production of viral cDNA without release of viral particles)
cell death
WHY?
CD4+ depletion include
the killing of virus-infected cells by CTLs
Killing of anti-gp120 antibody-coated cells by phagocytosis, Complement-mediated lysis, NK cell-mediated ADCC.
Cell fusion mediated by binding of an infected cell's gp120 to an uninfected cell's CD4 protein
Apoptosis due to induction of
FasL
Reduced generation of T cells by the thymus
Slide23Depletion in CD4 T cells is the primary cause of immunodeficiency in HIV-infected individuals
Memory T-cells responses such as to influenza virus
decline early in the disease progression
Loss of TH1
decrease or absence of DTH to intracellular pathogen increased susceptibility to TB
Effect both innate and adaptive function AIDS
Chronic exposure to HIV & other intestinal pathogens entering through damaged epithelium systemic inflammation inflammatory mediators cell death & damage to lymphoid organs
Invading gut microbes induce polyclonal B-cell activation (decline in TH) reduce in IgG and IgA(reduce in T cell dependent Ag)
Reduction in Innate response function dendritic cells function.
Slide24Slide25Course of AIDS
ACUTE CHRONIC AIDS
PHASE PHASE (<200cells/mm
3
)
Anti-HIV Ab/CTL
Dissemination of virus;
Seeding of lymphoid organs
Slide26Death
Opportunistic
infections
<200CD4
+
T cells/mm
3
Slide27Immunological abnormalities associated with HIV infection in different stages
Innate and inflammatory response:
Early:
infection of dendritic cells and transport of HIV to
draning
LN; some
disruction
of DCs and ILCs; inflammatory responses induced by HIV, microbes, and their products entering through damaged mucosal barriers, dead cells, and proinflammatory cytokines.
Late:
on going systemic inflammation; inflammatory cytokine TNF-
α
and IL-1
β
can cause cell death ; chronic cell activation contributes to tissue damage; infection of
microgilia
in brain can result in neurological disorders
T HELPER (TH) CELLS:
Early:
T helper (T) cells Depletion of CD4 T cells, especially memory T cells in the gut, where TH17 cells are targeted
Late:
Further decrease in CD4 T cell numbers and corresponding TH activities shift from
THl
to TH2 responses
Antibody production
Early:
Enhanced nonspecific IgG and IgA production
Late:
Reduced memory and marginal zone B cells. Reduced responses to antigens. Few broadly neutralizing anti-
HlV
antibodies. Decreased class switching, and therefore reduced
lgG
and
lgA
.
Delayed-type hypersensitivity
Early:
Highly significant reduction in proliferative capacity ofTH1 cells; shift from TH1 cells (which mediate DTH responses) to TH2 cells and reduction in skin-test reactivity
Late:
Elimination of DTH response; complete absence of skin-test reactivity
Slide29T CYTOTOXIC (T
C
) CELLS
Early:
Normal reactivity
Late
: Reduction but not elimination of CTL activity due to impaired ability to generate CTLs
fromTc
cells resulting
from reduced numbers ofTH1 cells and increased TREG cells, and reduced thymus function.
Slide30Diagnosis
RT-PCR (Reverse transcriptase –Polymerase Chain reaction) – detects viral load
ELISA (Enzyme linked immunosorbent assay)
Abs against HIV proteins (sensitive and specific)
Western Blot
Ab detection
Infected individuals who have developed Abs
(2 wks-6 months after infection) Positive
Vaccinated
CD4
+
:CD8+ T cell counts
Slide31Treatment of ID:
A
.Isolation from exposure to any microorganism.
B
. Replacement of missing protein as Ig, IFN-
γ
,….etc.
C
.Replacement of missing cell type by B.M. transplant.
D
. Replacement of defective gene as IL-2R
γ chain gene.
Slide32References :
Immunology , Kuby, seventh edition 2013
Immunology , Kuby, eighth edition 2019
Cellular and Molecular Immunology, Abul K. Abbas, 8
th
edition.