1. General Pathology: Immunodeficiency and Transplantation
Lorne Holland, M.D.

2. Immunodeficiency
A failure of the immune system to respond to usual stimuli
Causes are varied, but can be grouped into defects of humoral immunity, cell-mediated immunity, phagocytosis and complement
May be inherited (primary) or acquired (secondary)

3. 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

4. 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

5. 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

6. 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

7. 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

8. 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

9. 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

10. 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

11. 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

12. 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)

13. Complement Deficiency

14. 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.)

15. 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

16. HIV structure
gag, pol
env
p24

17. 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

18. 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

20. 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

21. 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)

22. 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

23. Pneumocystis pneumonia

24. HSV and Kaposi’s Sarcoma

25. Toxoplasmosis and Cryptosporidium

26. 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

27. 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

28. 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

29. 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

31. 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)

32. After Transplantation
Immunosuppression with one or more drugs
Cyclosporine & tacrolimus- blocks action of the phosphatase (caclineurin) which normally turns on IL-2 production
Sirolimus- blocks action of a kinase necessary for T-cell 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.)

33. 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

34. 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 B-cells (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)

35. 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

36. 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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42. 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)

46. Questions?