Introduction to the Immune System (The Immune System in Health and Disease) (Rheumatology) Part 8

Clinical Evaluation of Immune Function

Clinical assessment of immunity requires investigation of the four major components of the immune system that participate in host defense and in the pathogenesis of autoimmune diseases: (1) humoral immunity (B cells); (2) cell-mediated immunity (T cells,monocytes); (3) phagocytic cells of the reticuloendothelial system (macrophages), as well as polymorphonuclear leukocytes; and (4) complement. Clinical problems that require an evaluation of immunity include chronic infections, recurrent infections, unusual infecting agents, and certain autoimmune syndromes. The type of clinical syndrome under evaluation can provide information regarding possible immune defects. Defects in cellular immunity generally result in viral, mycobacterial, and fungal infections. An extreme example of deficiency in cellular immunity is AIDS. Antibody deficiencies result in recurrent bacterial infections, frequently with organisms such as S. pneumoniae and Haemophilus influenzae. Disorders of phagocyte function are frequently manifested by recurrent skin infections, often due to Staphylococcus aureus. Finally, deficiencies of early and late complement components are associated with autoimmune phenomena and recurrent Neisseria infections (Table 1-15).


Most current therapies for autoimmune and inflammatory diseases involve the use of nonspecific immune-modulating or immunosuppressive agents such as glucocorticoids or cytotoxic drugs. The goal of development of new treatments for immune-mediated diseases is to design ways to specifically interrupt pathologic immune responses, leaving nonpathologic immune responses intact. Novel ways to interrupt pathologic immune responses that are under investigation include the use of anti-inflammatory cytokines or specific cytokine inhibitors as anti-inflammatory agents; the use of monoclonal antibodies against T or B lymphocytes as therapeutic agents; the induction of anergy by administration of soluble CTLA-4 protein; the use of intravenous Ig for certain infections and immune complex-mediated diseases; the use of specific cytokines to reconstitute components of the immune system; and bone marrow transplantation to replace the pathogenic immune system with a more normal immune system (Table 1-16).




Classic Pathway

Clq, Clr, Cls, C4

Immune-complex syndromes,a pyogenic infections


Immune-complex syndromes,a few with pyogenic infections

C1 Inhibitor

Rare immune-complex disease, few with pyogenic infections

C3 and Alternative Pathway C3


Immune-complex syndromes,a pyogenic infections


Pyogenic infections


Neisseria infections


Pyogenic infections


Hemolytic uremic syndrome

Membrane Attack Complex

C5, C6, C7, C8

Recurrent Neisseria infections, immune-complex disease


Rare Neisseria infections

aImmune-complex syndromes include systemic lupus erythematosus (SLE) and SLE-like syndromes, glomerulonephritis, and vasculitis syndromes.

Cytokines and Cytokine Inhibitors

Anti-TNF-α monoclonal antibody (MAb) has been shown to be effective in both rheumatoid arthritis and ulcerative colitis. Use of anti-TNF-α antibody therapy has resulted in clinical improvement in patients with these diseases and has opened the way for targeting TNF-α to treat other severe forms of autoimmune and/or inflammatory disease. Anti-TNF-α MAb (infliximab and adalimumab) has been approved by the FDA for rheumatoid arthritis, plaque psoriasis, psoriatic arthritis, Crohn’s disease, and ankylosing spondylitis.

Other cytokine inhibitors include recombinant soluble TNF-α receptor (R) fused to human Ig and soluble IL-1 receptor (termed IL-1 receptor antagonist, or IL-1 ra). Soluble TNF-aR (etanercept) and IL-1 ra act to inhibit the activity of pathogenic cytokines in rheumatoid arthritis, i.e., TNF-α and IL-1, respectively. Favorable results have also been found with the use of IL-1 ra in autoinflammatory disease. Similarly, anti-IL-6, IFN-ß, and IL-11 act to inhibit pathogenic proinflammatory cytokines. Anti-IL-6 inhibits IL-6 activity, while IFN-ß and IL-11 decrease IL-1 and TNF- production.





Cytokines and Cytokine Inhibitors to Inhibit Immune Responses and Inflammation

Anti-TNF-α monoclonal antibody; humanized mouse chimeric MAb, infliximab, fully humanized MAb, adalimumab

Inhibit TNF-α

FDA approved for rheumatoid arthritis, Crohn’s colitis (infliximab); FDA approved for rheumatoid arthritis (adalimumab)

Recombinant TNF-receptor-Ig fusion protein (etanercept)

Inhibit TNF-α

FDA approved for rheumatoid arthritis, juvenile rheumatoid arthritis, psoriasis

Recombinant IL-1 receptor antagonist (IL-1Ra) (anakinra)

Inhibit ^-1α and -β

FDA approved for rheumatoid arthritis

Monoclonal Antibodies or Toxins Against T or B Cells

Anti-CD3 and T cell murine monoclonal antibody (OKT3)

Inhibit T cell function; induce T cell lymphopenia

FDA approved for treatment of cardiac and renal allograft rejection

Diphtheria toxin-IL2 fusion protein

Kills activated T cells

FDA approved for GVHD and transplant repertoire; understudy to kill T regulatory cell to embrace tumor vaccine efficacy

Humanized anti-CD3 monoclonal antibody (h0KT3 gamma-1)

Eliminates auto-reactive T cells

Human study underway in Type I diabetes, psoriasis

Humanized anti-CD25 (IL-2R) monoclonal antibody (daclizumab)

Eliminates activated T cells

FDA approved for graft versus host disease; studies underway in ulcerative colitis

Anti-CD40 ligand (CD154) monoclonal antibody

Inhibit CD40-CD40 ligand interaction; induces T cell tolerance

In primate trials for prevention of renal allograft rejection

Humanized anti-CD20 (anti-B cell) monoclonal antibody (rituximab)

Eliminates autoreactive B cells

Human study underway for treatment of ANCA+ vasculitis

Humanized anti-IgE monoclonal antibody (omalizumab)

Soluble T Cell Molecule

Block allergy causing IgE

Human study underway for allergy (hay fever, allergic rhinitis)

Soluble CTLA-4 protein Intravenous Immunoglobin

Inhibit CD28-B7-1 and B7-2 interactions; induces tolerance to organ grafts; inhibit autoimmune T cell reactivity in autoimmune diseases

FDA approved for rheumatoid arthritis.

In trials for preventing GVHD in bone marrow transplantation and for treatment of psoriasis, systemic lupus erythematosus, and certain forms of vasculitis.


Cytokines for Immune Reconstitutic

Reticuloendothelial cell blockage; complement inhibition; regulation of idiotype/anti-idiotype antibodies; modulation of cytokine production; modulation of lymphocyte production


FDA approved for Kawasaki’s disease and immune thrombocytopenia purpura; treatment of GVHD, multiple sclerosis, myasthenia gravis, Guillain-Barré syndrome, and chronic inflammatory demyelinating polyneuropathy supported by clinical trials



Hematopoietic Stem Cell Transplan

Induce proliferation of peripheral memory CD4+ and CD8+ T cells Induce renewed thymopoiesis


In trial for treatment of HIV infection

Under consideration for treatment of disease associated with T cell deficiency

Hematopoietic stem transplantation for immune reconstitution

Remove pathologic autoreactive immune system and replace with less autoreactive immunity

In clinical trials for systemic lupus erythematosus, multiple sclerosis, and scleroderma

Note: FDA, Food and Drug Administration; GVHD, graft-versus-host disease; ANCA, anti-neutrophil cytoplasmic antibody.

Of particular note has been the successful use of IFN-γ in the treatment of the phagocytic cell defect in chronic granulomatous disease. Intermittent infusions of IL-2 in HIV-infected individuals in the early or intermediate stages of disease have resulted in substantial and sustained increases in CD4+ T cells.

Monoclonal Antibodies to T and B Cells

The OKT3 MAb against human T cells has been used for several years as a T cell-specific immunosuppressive agent that can substitute for horse anti-thymocyte globulin (ATG) in the treatment of solid organ transplant rejection. OKT3 produces fewer allergic reactions than ATG but does induce human anti-mouse Ig antibody, thus limiting its use. Anti-CD4 MAb therapy has been used in trials to treat patients with rheumatoid arthritis. While inducing profound immunosuppression, anti-CD4 MAb treatment also induces susceptibility to severe infections. Treatment of patients with a MAb against the T cell molecule CD40 ligand (CD154) is under investigation to induce tolerance to organ transplants, with promising results reported in animal studies. Monoclonal antibodies to the CD25 (^-2α) receptor are being used for treatment of graft-versus-host disease in bone marrow transplantation, and anti-CD20 MAb (rituximab) is being tested for Wegener’s granulomatosis and microscopic polyangiitis that are associated with antineutrophil cytoplasmic antibodies (Chap. 10). Anti-IgE monoclonal antibody (omalizumab) is used in the treatment of asthma and is being tested for blocking antigen-specific IgE that causes hay fever and allergic rhinitis.

Tolerance Induction

Specific immunotherapy has moved into a new era with the introduction of soluble CTLA-4 protein, which is an approved treatment for rheumatoid arthritis (Chap. 5) and is being studied in a number of other clinical trials. Use of this molecule to block T cell activation via TCR/CD28 ligation during organ or bone marrow transplantation has showed promising results in animals and in human studies. Specifically, treatment of bone marrow with CTLA-4 protein reduces rejection of the graft in HLA-mismatched bone marrow transplantation. In addition, promising results with soluble CTLA-4 have been reported in the downmodulation of autoimmune T cell responses in the treatment of psoriasis; new trials of the drug are ongoing for treatment of systemic lupus erythematosus (Chap. 4),Wegener’s granulomatosis, giant cell arteritis, and Takayasu’s arteritis (Chap. 10).

Intravenous Immunoglobulin (IVIg)

IVIg has been used successfully to block reticuloendothelial cell function and immune complex clearance in various immune cytopenias such as immune thrombocytopenia. In addition, IVIg is useful for prevention of tissue damage in certain inflammatory syndromes such as Kawasaki disease (Chap. 10) and as Ig replacement therapy for certain types of immunoglobulin deficiencies. In addition, controlled clinical trials support the use of IVIg in selected patients with graft-versus-host disease, multiple sclerosis, myasthenia gravis, Guillain-Barré syndrome, and chronic demyelinating polyneuropathy (Table 1-16).

Stem Cell Transplantation

Hematopoietic stem cell transplantation (SCT) is now being comprehensively studied to treat several autoimmune diseases, including systemic lupus erythematosus, multiple sclerosis, and scleroderma. The goal of immune reconstitution in autoimmune disease syndromes is to replace a dysfunctional immune system with a normally reactive immune cell repertoire. Preliminary results in patients with scleroderma and lupus have showed encouraging results. Controlled clinical trials in these three diseases are now being launched in the United States and Europe to compare the toxicity and efficacy of conventional immunosuppression therapy with that of myeloablative autologous SCT.

Thus, a number of recent insights into immune system function have spawned a new field of interventional immunotherapy and have enhanced the prospect for development of specific and nontoxic therapies for immune and inflammatory diseases.

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