A. Subsets
[Figure] "Hematopoietic Lineages"

1. Characteristics
   1. Lymphocytes are white blood cells which have surface proteins specific for antigens
   2. An antigen (Ag) is any molecule which can stimulate an immune response
   3. The surface molecules on lymphocytes which bind antigens are called receptors
   4. Engagement of the receptors by antigens signals a response in the lymphocyte
   5. Lymphocytes can develop into long-lived cells which "remember" a previously encountered antigen; these are called memory lymphocytes
   6. Memory lymphocytes form the basis for strong secondary immune responses
2. T Lymphocytes
   1. Helper T Lymphocytes (Th Cells) - produce cytokines for B and CTL cell help
   2. Cytotoxic T Lymphocytes (CTL) - kill target cells
   3. Both types express T cell receptors (TCR) on their surface
   4. T lymphocytes with specific organ homing receptors are being identified
   5. Large granular lymphocytes - morphologically distinct type of peripheral T lymphocyte
   6. About 300 billion T cells in human adults
3. B Lymphocytes
   1. Mature B lymphocytes - express immunoglobulin (Ig, antibody) molecules on surface
   2. Plasma Cells - antibody (Ab) secreting B cells (terminally differentiated)
   3. About 150 billion B cells in human adults
4. Natural Killer Cells (NK)
   1. Related to CTL and large granular lymphocytes but most NK cells do not have TCR
   2. May recognize cells with non-self MHC molecules
   3. Antigen Specificity and Memory cells of this type have not been demonstrated
   4. About 30 billion NK cells in human adults
5. Distribution of Lymphocytes in Human Adults (Table 4, reference [26])

   Organ	T Cells	B Cells	NK Cells
   Thymus	15%	<1%	--
   Bone Marrow	10%	20%	20%
   Lymph Nodes	40%	40%	2%
   Spleen	10%	25%	40%
   Lung	10%	2%	35%
   Intestines	10%	10%	--
   Blood	2%	2%	5%

B. Lymphocyte Development [3,19]

1. Derived from pluripotent hematopoietic precursor cells in bone marrow (CD34+)
2. Early T lymphocytes migrate to thymus where they develop into mature T cells
   1. Thymus is required for negative and positive selection of T cells
   2. Negative selection means deletion (killing) of self-reactive (autoimmune) T cells
   3. Positive selection means enhancing development of certain T lymphocytes
   4. The positively selected thymocytes have TCR which recognize foreign antigens associated with self major histocompatibility complex (MHC) encoded antigens
   5. Interleukins 2 (IL2) and 15 (IL15) are critical for T cell development
3. Early B lymphocytes develop in the bone marrow to the mature B cell stage [2,14]
   1. Earliest B cells, called Pro-B cells, rearrange H chain genes to become pre-B cells
   2. Pre-B cells express µ Heavy (H) chains of the Ig only in their cytoplasm
   3. Pre-B cells then rearrange their Light (L) chains; H and L chains pair, go to surface
   4. Immature B cells, found in bone marrow, express surface Ig type M (IgM) and IgD
   5. Exposure of immature B cells to antigen (Ag) usually leads to apoptosis or anergy
   6. B cells which escape exposure to Ag in bone marrow migrate to peripheral tissue
   7. These mature B cells reside in peripheral lymphoid tissue, spleen > lymph nodes
   8. Antigen stimulated mature B lymphocytes develop into Ig secreting plasma cells
   9. Plasma cells live in bone marrow with lifespan of ~2-12 weeks
   10. IL7 and its receptor are critical for B cell development
   11. Fetal liver kinase 2 (FLK-2) ligand is also required for B cell development

C. T Lymphocytes [10,21,26]

1. Antigen Specificity
   1. The TCR is composed of an 2-protein antigen specific heterodimer non-covalently associated with TCR accessory proteins
   2. Most T cells have alpha-beta antigen binding TCR heterodimers
   3. Other T cells have gamma-delta TCR heterodimers which bind non-protein antigens
   4. Unlike immunoglobulins, TCR undergo minimal somatic mutation during development
   5. The alpha-beta TCR recognize antigen in association with MHC proteins
   6. The TCR is non-covalently associated with a complex of molecules called CD3
   7. Antigen, usually in the form of protein fragments or peptides, is "presented" to the T lymphocytes on the surface of antigen presenting cells (APC) in association with MHC
   8. APC's include macrophages, dendritic cells, and mature B lymphocytes (and others)
2. TCR Associated Proteins [19]
   1. The CD3 complex, composed of CD3g, CD3e, CD3zeta, CD3eta (non-covalent)
   2. The CD3 complex transduces signals to the lymphocytes
   3. Both CTL and Th cells have similar TCR complexes and nearly identical CD3 complexes
3. MHC Specificity
   1. Antigen (usually peptides) in association with MHC (on "presenting" cells) binds TCR
   2. Most Th cells have the CD4 polypeptide on their surface which binds to MHC Class II
   3. In general, Th cells are specific for antigen in association with MHC Class II
   4. Most CTL have CD8 heterodimers on their surface which binds to MHC Class I
   5. In general, CTL are specific for antigen in association with MHC Class I
   6. Other T cells recognize antigen in association with CD1 (a,b, or c) molecules
   7. CD1(a,b, or c) bind to foreign glycolipid antigens
4. Activation of T Lymphocytes [8]
   1. Binding of antigen in association with MHC to the TCR transduces a calcium signal
   2. CD3zeta and zeta associated protein (ZAP70) essential for T cell activation
   3. For full activation, other molecules on the APC bind to counterparts on T cell
   4. These "accessory" molecules have recently been discovered
   5. Blockade of these accessory cell interactions may transduce an inhibitory signal to the T lymphocytes
   6. It is critical that lymphocytes are appropriately activated against foreign invaders
   7. "Tolerance" for self antigens is "learned" both early and late in T cell development [22]
5. Accessory Molecule Interactions (see below) [8]
   1. CD28 or CTLA4 (CD152) on T cells binds to B7-1 or B7-2 on APC
   2. CD154 (gp39, CD40L) on T cells binds to CD40 on B cells (APC)
   3. CD2 on T cells binds to LFA-3 (CD58) on APC
   4. LFA-1 on T cells binds to ICAM-1 on APC
   5. CD45 on T cells binds to CD22 on B cells
   6. Abnormalities in certain accessory molecules leads to immunodeficiency disease
6. Organ Specific Homing of T Lymphocytes [15,26]
   1. Early data suggested organ specific homing of T lymphocytes
   2. However, most "organ specific" adhesion molecules are not specific
   3. Some T cells that home to skin express cutaneous lymphocyte antigen (CLA)
   4. Some gut-specific T cells express the integrin alpha4-beta7 (a4b7)
   5. Recent data suggest that trafficing into an organ is not regulated by specific molecules
   6. Adhesion molecules appear to be involved in tissue specific retention
   7. Blocking single adhesion molecules in vivo does not substantially affect T cells [26]
7. Induction of Anergy [8,21]
   1. Treatment of donor marrow with CD28 blockers in presence of irradiated recipient
   2. This provides first-signal stimulation, without coactivation signals
   3. Donor marrow becomes anergic specifically to recipient HLA/non-HLA antigens
   4. Incidence of GVHD is substantially reduced with this treatment
   5. Engraftment of treated donor bone marrow was not affected by treatment
   6. This kind of BMT is useful for patients without matched donors and with recurrent lymphoprofiliferative diseases
   7. Various autoimmune diseases are thought to be due to T cell intolerance [16]
8. Classification of Th Cells [7]
   1. All Th cells derived from Th0 cells which produce few or no cytokines
   2. Th1 cells: make interferon gamma (IFNg) and interleukin 2 (IL2)
   3. Th2 cells: make IL4, IL5, IL10
   4. Th3 cells: make transforming growth factor ß (TGFß); IL10+/-, IL4 -
   5. Th17 cells: make IFNg
   6. Tr1 (T regulatory) cells: make IL10; anti-inflammatory activity
9. Function of Th Cells
   1. Activation of Th cells leads to production of soluble proteins called cytokines
   2. These cytokines can affect T cell, B cell, monocyte, neutrophil, and other cells' functions
   3. Th1 cells (IFNg, IL2) stimulate killer cells and macrophages and dendritic cells
   4. IFNg also stimulates the production of certain antibody isotypes (especially IgG2)
   5. Th2 cells (IL4, IL10) stimulate eosinophils, antibody production, some suppression of Th1
   6. IL-5 and eotaxin (also from T cells) stimulate eosinophil production
   7. IL-4 stimulates B cells to produce IgG1, IgG4, and IgE
   8. Th2 cells have been implicated in allergic, hyper-IgE, eosinophilic conditions
   9. Persistence of Th2 cell responses to allergens in neonates associated with atopy [9]
   10. In addition, Th2 cells are found in parasitic infections and in lepromatous leprosy
   11. Absence of Th cells (mainly HIV infection) leads to chronic viral, fungal, and mycobacterial infections, with some increase in "usual" bacterial infections
10. Generation of Th Cells [7]
    1. Differentiation from Th0 cells due to activation and cytokine environment
    2. IL12, IFNg, Interferon gamma stimulate Th1 cell formation
    3. Cytokines such as IL4 (and IL13) strongly stimulate Th2 cell differentiation
    4. IL23 stimulates Th17 (highly inflammatory) cells
    5. FGXP3 stimulates Tr1
    6. Autoimmune disease may be due to abnormal bias in Th1/Th17 or Th2 subpopulations
    7. Molecular mimicry by micro-organisms may stimulate autoreactive T cells [16,22]
    8. Distinguishing self- from non-self- antigens is critical to prevent autoimmunity [22]
    9. More likely that T cells respond to antigen presentation in specific inflammatory or non-inflammatory environment and this leads to activation of non-self reactive cells
    10. Dendritic cells play a critical role in T cell education, activation, and inhibition
11. Environmental Bias to Th1 and Th2
    1. Exposure to early pathogens through day nursery early in life may bias toward Th1 [17]
    2. Likewise, exposure to significant levels of house-dust endotoxin at early age (which stimulates Th1 differentiation) appears to reduce the risk of developing allergies [18]
    3. Infections which induce Th1 such as mumps or hepatitis A associated with reduced rates of asthma and atopy
    4. Asthma, a Th2 disease, associated with reduced risk for diabetes mellitus type 1, vasculitis, rheumatoid arthritis (all Th1 1 autoimmune diseases) [29]
12. Function of CTL
    1. These are mainly CD8+ T cells, though CD4+ CTL have been demonstrated
    2. CD8+ CTL recognize antigen complexed with MHC Class I Molecules on target cell surface
    3. Bind to target antigen/MHC and lyse target cells
    4. Target cell lysis occurs by a mechanism similar to complement
    5. The CTL contains two types of killing proteins which are delivered to targets
    6. Perforins is a complement-like protein which forms holes in target membrane
    7. CTL granules also contain proteases (granzymes) which are injected into target cell
    8. CTL killing by perforin only leads to necrotic cell death
    9. Granzymes appear important for permitting CTL to kill by apoptotic cell death
    10. CTL kill virus infected cells, including HIV-1 virally infected targets
    11. Apoptotic death is rarely accompanied by any local inflammatory reaction
13. Large Granular Lymphocytes (LGL)
    1. Morphologically distinct subset of normal peripheral blood lymphocytes
    2. Mainly CD3+, TCR+, CD4-8+, CD57+, CD56- cells of true T lymphocyte lineage
    3. Other LGL are CD3-, TCR-, CD56+ NK cells, which also circulate
14. CD1d Restricted NK T Cells [5,6]
    1. Immunoregulatory group of T cells
    2. Also called invariant NKT cells
    3. CD1d restricted T cells express an invariant TCR which recognizes antigen+CD1d molecule
    4. These antigens are typically glycolipids related to alpha-galactosylceramide
    5. These cells may regulate Th1 helper cells
    6. Deficiency of NKT cells found in patients with sarcoidosis
    7. Increase in these NK T cells found in patients with asthma [23]
15. T Cells and Aging
    1. Elderly persons have reduced levels of both cellular and humoral immunity
    2. With aging, delayed type hypersensitivity (DTH) responses can decrease substantially
    3. Vitamin E given for 4 months can improve markers of T cell function including DTH [4]
16. Migration of T Lymphocytes [30]
    1. Sphingosine 1-phosphate (S1P) receptors play a role in lymphocyte migration
    2. S1P agonists result in lymphocyte sequestration in lymph nodes
    3. S1P agonists cause reversible lymphopenia by modifying lymphocyte migration
    4. Oral fingolimod is an S1P agonist which binds most of the 6 S1P receptors
    5. Fingolimod does not appear to increase in infection risk
    6. Fingolimod 1.25 or 5mg po qd for 6 months reduced relapses by ~50%, and reduced number of new T1-weighted MRI lesions by >40% in multiple sclerosis (MS) patients [24]
    7. Adverse effects: asympatomic aminotransferase elevations, dyspnea, nasal discharge, headache , diarrhea, nausea [24]
    8. Very promising oral agent for treatment of MS

D. B Lymphocytes [14,21]

1. These cells rearrange Ig genes and express Ig on their surface (sIg) [1]
   1. Mature B cells come from bone marrow, reside in lymphoid organs
   2. These cells proliferate and differentiate on exposure to antigen (activation)
   3. For full activation, most B cells require both sIg and second (accessory) signals
   4. These second signals include T-cell interactions (such as CD154-CD40) and cytokines
   5. Abnormal rearrangements may give rise to most lymphomas
   6. Distinguishing self- from non-self- antigens is critical to preventing autoreactive Abs from developing [22]
   7. Autoreactive B cells generally require T cell help
2. Signalling Mature B Cells Through sIg
   1. The B cell receptor consists of Ig H/L chains associated with the Ig(a) and Ig(b) proteins
   2. Antigen binds to the Ig portion and signals are transmitted through Ig(a/b) polypeptides
   3. This initiates a series of kinase reactions
3. Accessory Interactions Required for B Cell Activation
   1. Certain Ags, called "T-Independent" or TI Ags, can directly stimulate B cells
   2. TI Ags include many bacterial carbohydrate Ags and other highly repetative structures
   3. Proteins and some other Ags require additional signals to stimulate B cells
   4. These signals include direct T (or Mast) cell stimulation and/or cytokines
   5. IL-4 stimulates IgG4, IgE and IFNg stimulates IgG2 and inhibits IgE production
4. Activated B cells differentiate to Ab secreting plasma cells [2,19]
   1. B cell differentiation typically occurs in germinal centers in lymph nodes and spleen
   2. The cells then migrate to bone marrow where they reside as plasma cells
   3. Plasma cells are terminally differentiated
   4. They secrete about 1ng Ig per day per cell
   5. In the bone marrow, they comprise <1% of mononuclear cells
   6. Plasma cell numbers may increase (hyperplasia) or become malignant (myeloma)
   7. Myeloma cells proliferate slowly
5. Antibodies (Abs)
   1. Abs are Ig molecules and consist of heavy (H) and light (L) chains
   2. The Ab molecule is divided into Fab (antigen binding) and Fc (constant) portions
   3. The Fc portion, composed of H chain dimers, carries out effector functions of antibody
   4. The Fab portion of the antibody will bind antigen (in absence of MHC or other proteins)
   5. The isotype of the Ab depends on its H chain Fc region only
   6. In humans, eight isotypes exist: IgM, IgG1, IgG2, IgG3, IgG4, IgA1, IgA2, IgE
   7. Different isotypes carry out different functions
   8. In the blood, IgG is most prevalent (500-1500mg/dL), then IgM and IgA (~100mg/dL)
   9. On serum electrophoresis, IgG and IgA fractionate with gamma globulins
   10. IgM, a pentamer, fractionates with beta globulins
6. In a primary immune response, most antibodies (Abs) produced are of the IgM type
   1. IgM is a complement fixing antibody
   2. IgM exists as a pentamer of antibody chains, and thus is very large (~950kD MW)
   3. IgM can be a cold agglutinin and does not cross the placenta
7. In a secondary (booster) immune response, B cells switch their isotype to IgG or other type
   1. Some IgG's are complement fixing (for example, IgG1 and IgG2)
   2. Some IgG's are recognized by killer cells (through Fc receptors)
   3. IgG's cross the placenta
   4. IgAs are mainly involved in protection of mucosal surfaces (gut, oropharynx, genitalia)
   5. Plasma cells in bone marrow, spleen and lymph nodes produce mainly IgA1
   6. Plasma cells in the gut produce both IgA1 and IgA2
8. Main Roles of Abs in Disease
   1. Ab binding to pathogens is called "opsonization"
   2. Major role of Abs is in clearing bacterial (and some fungal) infections
   3. This is particularly true of staphylococci, encapsulated organisms, meningococcus
   4. Bound Abs can activate complement and/or attract killer cells, neutrophils, and macrophages
   5. Hypogammaglobulinemic patients often have chronic purulent bacterial infections
   6. Antibodies to self-antigens may cause certain autoimmune diseases [16]
9. Complement and Abs
   [Figure] "Complement Cascade"
   1. Certain Abs activate ("fix") complement leading to lysis of
   2. Patients lacking late complement components (C6-9) often have meningococcemia
   3. Patients lacking early complement components have an increased incidence of bacterial infections with encapsulated organisms
10. Current vaccines primarily stimulate Ab production [28]
    1. Polysaccharide vaccines stimulate primarily T-cell independent Ab responses
    2. Live virus vaccines stimulate T-cell dependent Ab responses and some cytotoxic T cells
    3. Attempts to enhance duration of responses, particularly with polysaccharide vaccines, are under investigation

E. Immune Response to Infections

1. Bacterial
   1. Bacterial coat proteins stimulate neutrophil activation initially
   2. In addition, non-specific APC (macrophages, dendritic cells) pick up bacterial antigens
   3. These are presented to T lymphocytes, which then produce cytokines
   4. Some bacterial products directly stimulate B cells, macrophages and other cell types
   5. Bacterial lipopolysaccharide (LPS) is the best known of such molecules
   6. IL-12 is produced by macrophages and strongly directs the Th response towards Th1
   7. CTL are usually not stimulated to a significant degree
   8. Acute bacterial infections show large numbers of neutrophils (may have band forms)
   9. Chronic bacterial infections show more Th cells (and some CTL) and plasma cells
   10. Bacterial and other microbial products can also stimulate leukocytes through Toll-like receptors (which can replace cytokine second signals) [15]
2. Mycobacterial
   1. Chronic, difficult to eradicate infections usually stimulate lymphocytes
   2. Acute infections show mainly neutrophils, but Th cells rapidly increase
   3. If Th1 cell response is generated, the infection is often contained
   4. The Th1 cells produce IFNg, other lymphokines which stimulate macrophages
   5. Th cells and macrophages may form granulomas
   6. If Th2 cells predominate, infections may not be contained, as in Lepromatous Leprosy
3. Viral
   1. Viruses infect cells and viral peptides are expressed on the surface
   2. Some viral peptides are expressed in association with MHC Class I molecules
   3. Once CTL are generation occurs, the CTL can lyse infected cells
   4. Th cells, mainly Th1, are stimulated by APC's which express viral peptides with Class II
   5. Antibody plays a major role in preventing initial viral infection, but not in killing infected cells
   6. Interferon gamma, alpha and beta play a major role in anti-viral responses
   7. Acute viral infections stimulate neutrophils, but lymphocytes rapidly predominate
4. Fungal
   1. Acute fungal infections stimulate neutrophils, but lymphocytes rapidly predominate
   2. Main containment of infections is via neutrophils and IFNg activated macrophages
   3. IFNg from Th1 cells; unclear role of antibodies in most cases
   4. Patients with neutropenia are highly susceptible to fungal infections
5. Parasites
   1. Persistance of most parasites appears to correlate with Th2 cell predominance
   2. The Th2 cells produce cytokines which stimulate IgE and eosinophilia

F. Leukocyte Trafficking [12,13,26]

1. T cells constantly move in and out of the circulation
   1. There are ~10 billion T cells in the blood at any time
   2. The half-life of T cells in the blood is ~30 minutes
   3. There is little data to support organ specific homing of T cells [26]
   4. Instead, once in tissues, lymphocytes remain there based on adhesion molecule binding
   5. Lymphocytes may be "imprinted" to more likely return to organ where they encountered stimulating antigen [27]
2. Migration of leukocytes to areas of infection and inflammation is complex
   1. Leukocytes must migrate across blood vessels into site of infection
   2. Leukocyte-endothelium interactions are critical to these events
   3. Gut lymphocytes often migrate first to portal sinusoids in liver, then systemically
3. Migration of leukocytes is a sequential multistep process [26]
   1. Specific surface molecules on leukocytes and endothelia are involved at each step
   2. Most migration occurs through venules
   3. Cell velocity in venules is ~500µm/sec
   4. Circulating leukocytes first begin rolling along endothelium
   5. Rolling is mediated through selectins
   6. Tethering of leukocytes to endothelium occurs mainly through integrins
   7. Firm adhesion then occurs with velocities <0.2µm/sec
   8. Finally, extravasation occurs utilizing PECAM-1 and other molecules
   9. Integrins and immunoglubulin superfamily proteins critical for these processes
4. Similar mechanisms are involved in infectious and non-infectious inflammation
5. Organ Specific Homing [15,26]
   1. Subpopulation of T cells that are retained in the skin have been identified
   2. These subpopulations express cutaneous lymphocyte antigen (CLA) and CCR4
   3. CLA+ cells make up 10-15% of all circulating peripheral blood T cells
   4. CLA+ T cells may express either CD4 or CD8 and bind to E-selectin
   5. Similarly, cells expressing alpha4beta7 integrin are more likely retained in the gut
   6. Cells expressing VAP-1 (vascular adhesion protein 1) home preferentially to liver [27]
   7. Highly specific homing of T cells to organs is difficult to demonstrate in humans [26]

G. Leukocyte-Endothelial Adhesion Molecules [12]

1. Inflammation as a response to tumors does occur
   1. In most cases, it is "low-grade", chronic inflammation
   2. Includes production of growth and angiogenic factors that stimulate tissue repair
   3. These factors can also promote tumor survival, growth, and proliferation
2. Immune Mediated Tumor Rejection
   1. Occasionally, inflammation becomes more rubust, similar to acute inflammatory processes
   2. In these cases, the immune response can induce a regression in the cancer
   3. Converting a pro-tumorigenic to an anti-tumorigenic environment is under study
3. Mechanisms
   1. Most cancer related inflammation is due to innate immune system
   2. B lymphocytes, of the adaptive immune system, can contribute to carcinogenesis
   3. However, many immunodeficiency syndromes are associated with increased cancer risk
   4. This may be driven by high rates of chornic inflammation in immunodeficiency
4. Therapeutic Potential
   1. Stimulating the immune system has been modestly successful in reducing cancers
   2. IL2 therapy has some efficacy in renal cancer and melanoma, with some long term cures
   3. IFNa therapy has some efficacy in these cancers as well
   4. Vaccines are under development

I. Tumors of Lymphocytes [25]

1. Lymphocytic and lymphoblastic leukemias
   1. Acute lymphoblastic leukemia (ALL) T or B or null cell types
   2. Chronic lymphocytic leukemia (CLL) - mostly B cell type, some T cell
2. Lymphomas
   1. Non-Hodgkin's - mostly B cell derivatives
   2. Hodgkin's - B cell derivatives
3. Several diseases can exist as lymphoma, leukemia variants, or both
   1. T cell ALL and lymphoblastic lymphoma
   2. B cell ALL and diffuse small non-cleaved cell lymphoma
   3. Chronic lymphocytic leukemia (CLL) and diffuse small lymphocytic lymphoma

J. Idiopathic CD4+ T Lymphopenia

1. Characteristics and Symptoms
   1. Recurrent infections
   2. CD4+ T cell count <400/µL
   3. Ratio of CD4+ to CD8+ cells <1.0
   4. HIV Negative
2. Treatment
   1. Similar to HIV for prophylaxis of opportunist infections; no data on anti-virals
   2. Rule out other causes of immunodeficiency
   3. No known etiology at this time makes direct treatment difficult
   4. Symptomatic and supportive therapy recommended
   5. IFNg may reduce incidence of bacterial infections
   6. Bone marrow transplantation may be curative

References

1. Schwartz RS. 2003. NEJM. 348(11):1017
2. Bataille R and Harousseau JL. 1997. NEJM. 330(23):1657
3. Stock W and Hoffman R. 2000. Lancet. 355(9212):1351
4. Meydani SN, Meydani M, Blumberg JB, et al. 1997. JAMA. 277(17):1380
5. Ho LP, Urban BC, Thickett DR, et al. 2005. Lancet. 365(9464):1062
6. Jiang H and Chess L. 2006. NEJM. 354(11):1166
7. Baumgart DC and Carding SR. 2007. Lancet. 369(9573):1627
8. Sharpe AH and Abbas AK. 2006. NEJM. 355(10):973
9. Prescott SL, Macaubas C, Smallacombe T, et al. 1999. Lancet. 353(9148):196
10. Mantovani A, Romero P, Palucka AK, Marincola FM. 2008. Lancet. 371(9614):771
11. Guinan EC, Boussiotis VA, Neuberg D, et al. 1999. NEJM. 340(22):1704
12. Kevil CG and Bullard DC. 1999. Am J Med. 106(6):677
13. Rabb H and Bonventre JV. 1999. Am J Med. 107(2):157
14. Chiorazzi N, Rai KR, Ferrarini M. 2005. NEJM. 352(8):804
15. Robert C and Kupper TS. 1999. NEJM. 341(24):1817
16. Albert LJ and Inman RD. 1999. NEJM. 341(27):2068
17. Kramer U, Heinrich J, Wjst M, Wichmann HE. 1999. Lancet. 353(9151)450
18. Gereda JE, Leung DYM, Thatayatikom A, et al. 2000. Lancet. 355(9216):1680
19. Rudd CE. 2006. NEJM. 354(18):1874
20. Delves PJ and Roitt IM. 2000. NEJM. 343(1):37
21. Delves PJ and Roitt IM. 2000. NEJM. 343(2):108
22. Kamradt T and Mitchison NA. 2001. NEJM. 344(9):655
23. Akbari O, Faul JL, Hoyte EG, et al. 2006. NEJM. 354(11):1117
24. Kappos L, Antel J, Comi G, et al. 2006. NEJM. 355(11):1124
25. Caligaris-Cappio F. 2001. Lancet. 358(9275):49
26. Westermann J, Engelhardt B, Hoffmann JC. 2001. Ann Intern Med. 135(4):279
27. Grant AJ, Lalor PF, Salmi M, et al. 2002. Lancet. 359(9301):150
28. Kelly DF, Pollard AJ, Moxon ER, et al. 2005. JAMA. 294(23):3019
29. Tirosh A, Mandel D, Mimouni FB, et al. 2006. Ann Intern Med. 144(24):877
30. Massberg S and von Andrian UH. 2006. NEJM. 355(11):1089