Transcript General Pathology: Acute Inflammation

General Pathology:
Immunodeficiency and Transplantation
Lorne Holland, M.D.
[email protected]
Immunodeficiency
• A failure of the immune system to respond
to usual stimuli
• Causes are varied, but can be grouped
into defects of humoral immunity, cellmediated immunity, phagocytosis and
complement
• May be inherited (primary) or acquired
(secondary)
Humoral Deficiencies
• Infancy
– At birth, essentially all circulating immunoglobulins
are maternal IgG
– As infant ages, maternal immunoglobulins are
removed from circulation
– At the same time, baby is ramping up production
of its own immunoglobulins (IgG, IgM, IgA)
– Early on, the decline in maternal concentrations
happens a little faster than the infant can
synthesize new immunoglobulins
– Around 3-6 months synthesis rates increase and
total immunoglobulin concentrations begin to rise
Humoral Deficiencies
• X-linked agammaglobulinemia (Bruton’s)
– Failure of precurssor cells to differentiate into
B-cells because of a lack of Bruton’s tyrosine
kinase
– Responsible defective gene on X chromosome
– Initally present with recurrent pyogenic
(bacterial) infections between 4 months and 2
years
– Replacement (transfusion) of pooled
immunoglobulin can treat
– Increased risk of autoimmune diseases
Humoral Deficiency
• Hyper IgM syndrome
– Normal or elevated levels of IgM, but no other
immunoglobulins
– Most often, lack of CD40 ligand on T-cells leads to
no isotype switching by B-cells and poor
stimulation of macrophages
– CD40L is located on X chromosome so 70% of
cases are seen in males
– Recurrent pyogenic infections and Pneumocystis
pneumonia
– Treat with pooled immunoglobulin and
prophylactic antibiotics or BMT
Humoral Deficiency
• Selective IgA deficiency
– Normal or high immunglobulin concentrations
expect IgA which is low or completely absent
– Typically clinically silent though those with no
IgA may have increased rates of respiratory
and GI infections
– Those with no IgA may also have anaphylactic
reactions to IgA in blood products
– At higher risk for developing autoimmune
diseases
Humoral Deficiency
• Common variable immunodeficiency
– Low concentrations of one or more kind of
immunoglobulin
– Usually much more modest increase in rate of
pyogenic infections and so may not be
diagnosed until adulthood
– Also at increased risk for a number of
autoimmune diseases and lymphoid
malignancies
Cell-mediated Deficiency
• Severe combined immunodeficiency
– Impaired T-cell function which can also cause
secondary impaired B-cell function
– Autosomal recessive form due to mutations in
cytokine receptors which stimulate growth (25%)
– X-linked form due to mutation in adenosine
deaminase necessary for DNA synthesis (50%)
– Present in the first weeks or months of life with
recurrent infections of all kinds
– In absence of BMT (or gene therapy), life
expectancy is typically 1-2 years
Cell-mediated Deficiency
• Thymic hypoplasia (DiGeorge syndrome)
– Underdevelopment (absence) of the thymus
leaves few places for T-cells to be “educated”
– Despite this, immunodeficiency is typically rather
mild except in total absence
– Susceptible to fungal, viral, and protozoal
infections (not typical bacteria species)
– Death can occurs due to associated abnormalities
(e.g. cardiac malformations)
– Maybe prophylaxis with sulfamethoxazole/
trimethoprim (Bactrim, Septra)
– Transplantation of thymic tissue may be helpful
Cell-mediated Deficiency
• Wiscott-Aldrich syndrome
– Defects in both T-cells and B-cells along with
thrombocytopenia and eczema
– Exact mechanism is unknown, but responsible
gene is on the X chromosome and codes for
proteins involved in cytoskeletal structure
– Untreated, death in early childhood
– BMT is only effective treatment
– Increased risk of hematologic malignancies
Phagocytosis Deficiency
• Chronic granulomatous disease
– Failure of neutrophils to produce sufficient
amounts of bacteriocidal products (reactive
oxygen species) after phagocytosis
– Typically, presents as severe, recurrent skin
infections by bacteria (staph) or fungus
(candida, aspergillus) and/or pneumonia
Phagocytosis Deficiency
• Chronic granulomatous disease (cont)
– Ultimately, spreads systemically and form
abscesses and granulomas in multiple organs
(liver, bones)
– Maybe prophylaxis with sulfamethoxazole/
trimethoprim (Bactrim, Septra)
– Aggressive, early treatment of any potential
infections
– Interferon therapy (may increase amounts of
bacteriocidal products synthesized)
Complement Deficiency
Complement Deficiency
• C1, C4 and/or C2 present with autoimmune
symptoms
• C3 presents with severe, recurrent bacterial
infections (convergence of classic and alternate
pathways as well as chemotaxis, opsonization)
• C5, C6, C6, C8 (MAC) presents with recurrent
infections (meningitis, sepsis, arthritis) with
encapsulated bacteria (Neisseria sp.)
Secondary Immunodeficiency
• Acquired Immunodeficiency Syndrome
– Caused by the human immunodeficency
retrovirus (RNA)
– Two proteins on outside gp120 and gp41
– Inside: p24, RNA, protease, reverse
transcriptase, integrase
– Three key retroviral genes: gag, pol and env
– These gene products (proteins) must be
cleaved by protease to become functional
HIV structure
gag, pol
env
p24
Secondary Immunodeficiency
• Acquired Immunodeficiency Syndrome
– Virus adheres to cells via interaction of gp120
and CD4 with help from chemokine receptors
(CXCR4 and/or CCR5)
– T-cells, macrophages and other APCs are
most vulnerable
– gp41 penetrates membrane and allows for
transfer of viral RNA
Secondary Immunodeficiency
• Acquired Immunodeficiency Syndrome
– Viral RNA reverse transcribed into DNA
– Viral DNA is inserted into host DNA by
integrase
– Inserted DNA remains latent until infected cell
is stimulated (by normal means) and begins
to divide
• http://www.youtube.com/watch?v=9leO2
8ydyfU
Secondary Immunodeficiency
• Acquired Immunodeficiency Syndrome
– Acute infection causes flu-like symptoms in some,
but not all people
– Although destruction of CD4+ cells is occurring,
symptoms may not appear for several years
– Time to seroconversion depends on testing method
• Typical anti-HIV antibody screens  ~3 weeks
• HIV p24 antigen  ~2 weeks
• HIV RNA  ~1 week
Secondary Immunodeficiency
• Acquired Immunodeficiency Syndrome
– After latent phase, clinical manifestations vary
– Generalized lymphadenopathy, diarrhea, night
sweats, weight loss
– Meningitis, encephalopathy, neuropathy, dementia
– Unusual, opportunistic infections- Pneumocystis
pneumonia, severe CMV or HSV, cerebral
toxoplasmosis, unusual mycobactrial species,
unusual fungal species, GI cryptosporidum
– Tumors- Kaposi’s sarcoma (HSV 8), non-Hodkins
lymphoma (EBV), cervical cancer (HPV)
Secondary Immunodeficiency
• Acquired Immunodeficiency Syndrome
– Treatment options
• Nucleoside reverse transcript inhibitors
• Non-nucleoside reverse transcript inhibitors
• Protease inhibitors
• Entry/fusion inhibitors (gp120, gp41,
chemokine receptors)
• Integrase inhibitor
Pneumocystis pneumonia
HSV and Kaposi’s Sarcoma
Toxoplasmosis and Cryptosporidium
Secondary Immunodeficiency
• Either due to loss of immunoglobulins
– Nephrotic syndrome
– Protein-losing enteropathy
• Or due to impaired synthesis of
immunoglobulins and/or cells
– Severe malnourishment
– Destruction of bone marrow (e.g.
lymphoproliferative disorders)
– Viral infections (CMV, measles, mono, et al.)
– Iatrogenic immunosuppression
Organ Transplantation
• Normal immunity helps protect the body
from invasion by microorganisms and
provides surveilance for development of
cancer
• These same defense mechanisms will
attack “foreign” transplanted tissue
Organ Transplantation
• Successful organ transplantation requires
– Sufficient pharmacologic suppression of the
immune system to prevent rejection
– Without oversuppression which would
predispose patients to opportunistic infections,
tumors and graft-versus-host disease
Organ Transplantation
• Human leukocyte antigens (HLA), a.k.a
MHC proteins, are strongly antigenic
• One gene is inherited from each parent for
each HLA class (MHC I- A, B, C and MHC
II- DP, DQ, DR)
• So a cell may express up to 12 different
HLA proteins
• A, B and DR are the most important
Before Transplantation
• Find organ donor who matches as many
HLA alleles as possible
• Depending on organ, may need to use
ABO (blood type) compatible organ as well
• Screen recipient for presence of existing
antibodies to foreign HLA types
• Find suitable live donor (kidney, liver,
lung, bone marrow) or cadaveric donor
(above plus heart, pancreas)
After Transplantation
• Immunosuppression with one or more drugs
– Cyclosporine & tacrolimus- blocks action of the
phosphatase (caclineurin) which normally turns on IL2 production
– Sirolimus- blocks action of a kinase necessary for Tcell proliferation (and activation)
– Azathioprine & mycophenolate inhibit DNA synthesis
– Monoclonal antibodies (end in “ab”, Muromonab) bind
to T-cell proteins and lead to destruction by other
immune cells or bind to and block IL-2 receptor
– Corticosteroids increase synthesis of proteins which
inhibit transcription of multiple cytokines (IL-2, et al.)
After Transplantation
• Monitor for rejection
– Hyperacute  antibodies to proteins on
transplant are present at time of transplantation,
rapid destruction (within minutes to hours) of
transplantion
– Acute  failure of immunosuppression so that
antibodies develop in the weeks or months
following transplantation
– Chronic  immunosuppression can not (yet) be
perfect, small amounts of damage accumulate
over years and eventually destroy transplant
After Transplantation
• Rejection, direct
– Donor APCs do what they do, but interact with
recipient CD4 T-cells which have entered the
transplant
– Recipient CD4 cells recognize MHC II on donor
APCs as foreign
– CD4 cells recruit (cytotoxic) CD8 T-cells and Bcells (which differentiate into plasma cells and
make antibodies)
– CD8 cells mediate cytotoxicity via foreign MHC I
(which is on all nucleated cells, importantly
endothelial cells)
After Transplantation
• Rejection, indirect
– Donor HLA antigens either enter the blood
stream or are carried by donor dendridic cells
(APCs) to recipient lymphoid tissue
– Recipient CD4 T-cells recognize the foreign
antigens, enter circulation, find their way to
the transplant, and cause inflammatory
response
– Again, damage to endothelium is as important
as damage to organ itself
Graft-versus-host Disease
• Highest risk after BMT, but can occur after
any transplant, including transfusion
• Donor lymphocytes in the transplant or
transfusion recognize the recipient as
foreign, but the recipient fails to recognize
the donor lymphocytes as foreign
• The recipient lymphocytes fail to act either
because the donor cells do not look
foreign to them or they are defective in
number or function
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Graft-versus-host Disease
• Any tissue can be affected, but liver, skin
and GI tract are particularly affected
• Present with jaundice, rash and/or bloody
diarrhea
• May be acute with rapid increase of
symptoms or chronic with insidious
progression
• Treat with increased immunosuppression
and/or immunomodulation
(photopheresis)
Questions?