General Pathology: Immunodeficiency and Transplantation

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

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

19. http://www.youtube.com/watch?v=9leO28ydyfU

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?