The Journal of Allergy and Clinical Immunology
Volume 120, Issue 2 , Pages 263-270, August 2007

Advances in basic and clinical immunology in 2006

  • Javier Chinen, MD, PhD

      Affiliations

    • Corresponding Author InformationReprint requests: Javier Chinen, MD, PhD, Department of Pediatrics, Allergy and Immunology Section, Baylor College of Medicine, Texas Children's Hospital, 1102 Bates St, Houston, TX 77030.
    • ,
  • William T. Shearer, MD, PhD

From the Department of Pediatrics, Allergy and Immunology Section, Baylor College of Medicine

Received 17 May 2007; accepted 22 May 2007. published online 26 June 2007.

Houston, Tex

Article Outline

This article reviews the progress in the field of basic and clinical immunology in 2006, focusing on the articles published in the Journal. The role of Toll-like receptors in the immune response was explored in detail in several articles. The knowledge gained in these investigations is being used to develop strategies that enhance the immunogenicity of vaccines to prevent infectious diseases and to have an immunomodulatory effect on allergic diseases. Other components of the innate immunity reported on were the recognition of allergens with lipid-derived motifs by CD1d-restricted T cells and the role of dendritic cells in the development of an allergic response. More than 120 primary immunodeficiencies were defined at a molecular level, and biological agents such as TNF-α antagonists and IFN-α were shown to have therapeutic use. New anti-HIV drugs that block cell entry were proven to be effective, thus offering alternative therapies to respond to the development of multidrug-resistant HIV strains. The modern understanding of immunologic concepts is helping to elucidate the mechanisms of defense against viruses, bacteria, and parasites; as a result, strategies to improve management and prevention continue to emerge.

Key words: Immunology, Toll-like receptors, CD1d T cells, immunomodulators, primary immunodeficiencies, drug allergy, angioedema, vaccines

Abbreviations used: CF, Cystic fibrosis, CVID, Common variable immunodeficiency, HAE, Hereditary angioedema, NK, Natural killer, PGE2, Prostaglandin E2, PID, Primary immunodeficiency, SEB, Staphylococcal exotoxin B, TLR, Toll-like receptor

 

The amount of scientific progress in the fields of basic and clinical immunology continues to accumulate at a remarkable speed. We have summarized the articles considered most relevant to the readers of the Journal and provided an overall view of the current most active research areas. This article is divided in 2 parts, describing first the scientific advances in basic immunology (Table I), followed by progress reported in clinical immunology (Table II).

Table I. Key advances in basic immunology in 2006
1. Pathogen infections may induce TH1-type immunity through TLR signaling, supporting the hygiene hypothesis in allergic diseases.
2. Strategies to improve the efficiency of DNA vaccines for allergy immunotherapy include the use of ubiquitination and viral replicase.
3. Peptides conjugated to viral-like particles and immunostimulatory sequences are promising candidate vaccines for allergic disease.
4. Allergen lipid moieties bind CD1d receptors in activate γδ-T cells.
5. CD11c+ dendritic cells, IL-15, CD30 surface molecule, and complement C3 protein were found to be essential in the allergic response in animal models.
Table II. Key advances in clinical immunology in 2006
1. CD103 may be a useful marker of regulatory T cells.
2. More than 120 primary immunodeficiencies have been molecularly defined.
3. Mutations in the gene encoding the RNA component of mitochondrial RNAse processing, responsible for the cartilage-hair hypoplasia syndrome, may cause Omenn syndrome.
4. Lack of response to androgens in hereditary angioedema may be explained by an homozygous genetic defect.
5. New anti-HIV drugs targeting viral cell entry demonstrated in vitro activity to decrease HIV replication.

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Advances in basic immunology 

Toll-like receptors 

Kaisho and Akira1 reviewed in depth the significance of Toll-like receptor (TLR) signaling in the immune response and described the relative specificity of TLRs to bind molecules derived from infectious and noninfectious agents, resulting in the activation of immune cells and the secretion of immunomodulatory cytokines. Ten different TLRs recognize various groups of molecules, known as microorganism-associated molecular patterns: single-stranded RNA binds to TLR-7 and TLR-8, LPS binds to TLR-4, and flagellin binds to TLR-5. TLR-2 is a receptor for lipoproteins and lipoteichoic acid, TLR-3 binds double-stranded RNA, and TLR-9 is specific for DNA containing unmethylated CpG islands, found in bacterial DNA (Fig 1). Studies on TLR-9 signaling have demonstrated specific induction of the TH1 immunity phenotype. The concept of the regulation of the immune response by TLRs binding supports the hygiene hypothesis in the development of allergic diseases, which proposes that a predominance of a TH1 cytokine environment secondary to immune responses to infections may reduce the risk of developing TH2 conditions leading to the development of atopic disease. A review by Schaub et al2 and the accompanying editorial3 in the same issue commented on the complexities of this hygiene hypothesis, which takes into consideration not only the genetic components of the individual and the microbe but also some interaction factors including time and amount of exposure. The authors of both articles acknowledge there is no unifying theory that can explain the present conflicting data, such as the association of viral infections with both increased airway hyperactivity and protection from atopic diseases. Horner4 further focused on the role of TLR-4 and TLR-9 ligands to explain the modulation of the immune system into favoring TH1 responses. He proposed that the development of pharmacologic molecules to stimulate TLR-9 may be useful to avoid the development of atopy. Taylor et al5 tested whether exposure to the TLR-2 ligands lipoteichoic acid and heat-killed Staphylococcus aureus may influence the cytokine response of human mononuclear cells to allergens. This work demonstrated a decrease of dust mite–specific IL-5 and IL-13 levels, but only on dust mite–sensitive individuals, possibly because of the small amount of these cytokines that were secreted in normal controls. Hoarau et al6 detected high production of IL-10 by human dendritic cells induced by supernatants from Bifidobacterium species that was mediated by TLR-2 signaling, but not TLR-4, TLR-7, or TLR-9.

  • View full-size image.
  • Fig 1. 

    TLRs and the microbial antigen recognition patterns. Simplified diagram of the different TLRs' signaling through MyD88-dependent and -independent pathways. dsRNA, Double-stranded RNA; ssRNA, single-stranded RNA; TRIF, TLR–associated activator of IFN.

Fili et al7 used an immunomodulator, resiquimod, and a modified adenine molecule, benzyl adenine, to show induction of IL-12 and IL-10 through nuclear factor-κB signaling in human CD14+ mononuclear cells. These investigators also used HEK293 epithelial cells to determine that TLR-7 was the receptor providing the cell signal for cytokine secretion. Both resiquimod and benzyl adenine molecules induce the switch of allergen-specific T cells to (1) present the TH1 phenotype, (2) upregulate expression of T-bet and IFN-γ, and (3) downregulate GATA-3 and IL-4 expression. The authors described the potential of using these 2 molecules as adjuvants to modulate allergic reactions. Other investigations exploring the role of TLRs showed that the chemotactic response of dendritic cells to cysteinyl leukotrienes was decreased if induced to mature with LPS (through TLR-4), but not with poly-inosine, (mediated by TLR-3),8 and that the interleukin receptor-associated kinase 4 is involved in secretion of IFN-α mediated by signaling through TLR-3, TLR-7, TLR-8, and TLR-9.9

Development of DNA-based and peptide-based vaccines for allergy immunotherapy 

Several strategies are being investigated to induce a change in the immune response to allergens and inhibit IgE-mediated reactions. Some of these approaches use the ability of bacterial DNA to stimulate the development of TH1 responses. Sudowe et al10 reported their ability to induce DNA vaccine expression specifically in dendritic cells when delivered by a gene gun. They demonstrated both a prophylactic and a therapeutic effect by inducing a predominant TH1 cytokine secretion of lymph node and spleen cells, which caused a decrease of specific IgE in mice sensitized to β-galactosidase. The use of relatively small amounts of DNA to avoid IgE antibody responses was investigated by using a DNA vaccine simultaneously encoding the Sindbis virus replicon and the peptide Phl p 5, the major timothy grass pollen allergen. Plasmid DNA with or without the Sindbis virus replicase was administered intradermally to mice, followed by sensitization and challenge with Phl p 5.11 TH1 responses were induced; however, they were 100-fold stronger when the replicon unit was used than when the peptide was used alone. The authors suggested the use of this approach to reduce the amount of DNA needed to stimulate the TH1 response. Using the concept of protein degradation by ubiquitination, Bauer et al12 reported their efforts to decrease the anaphylaxis risk in using vaccines for allergic diseases. They compared the immunogenicity of a DNA vaccine encoding Bet v 1 and another encoding an ubiquitinated variant of the same protein. Both DNA vaccines were able to protect mice from IgE sensitization to Bet v 1 and were able to stimulate T-cell proliferation and production of TH1 cytokines. However, the ubiquitinated vaccine induced significantly lower specific IgE titers than the wild-type protein in naive and in Bet v 1–sensitized animals. This novel strategy may usher in a new level of safety in the development of DNA vaccines.

Higgins et al13 used immunostimulatory DNA sequences conjugated to the ragweed allergen Amb a 1 at different molecular ratios to immunize mice. Immunostimulatory DNA contains several copies of the CpG motif, which binds to TLR-9 and results in the induction of a TH1 immune response. A low compound ratio of immunostimulatory DNA to Amb a 1 protein was defined as 2:1, a medium ratio was 3:1 to 8:1, and a high ratio was 5:1 to 10:1. All compound ratios induced a strong TH1 responses; however, a low compound ratio induced high antibody titers of the IgG1 type, medium ratios induced IgG2a, and high ratios induced very low antibody titers. They were able to demonstrate a 222-fold reduction of the sensitivity of human leukocytes to Amb a 1, a characteristic that may be useful for avoiding anaphylactic reactions in DNA vaccine therapy. An alternative immunogenic approach consisting of viral-like particles coupled with a peptide derived from the allergen Der p 1 was tested in human volunteers. Strong specific IgG1 and IgG3 responses were demonstrated without detectable IgE induction, thus showing both safety and efficacy in preventing TH2 sensitization to the allergen.14

Seidel-Guyenot et al15 designed an immunization protocol to inhibit the development of contact hypersensitivity based on the concept of low zone tolerance. They measured ear swelling in mice after sensitization with 10-fold serial dilutions of the hapten 2,4,6-trinitro-1-chlorobenzene and found the optimal low concentration of hapten that elicited the smallest inflammation after challenge, using epicutaneous, intravenous, and oral routes. Using CD4 knockout and IL-10 knockout mice models, these researchers demonstrated that both IL-10 and CD4+ T cells were important to achieve immune tolerance with the optimal low-dose treatment. An analysis of cytokine secretion by isolated CD4+ and CD8+ T cells after sensitization showed that CD8+ T cells were mostly responsible for the measured IL-10. They also showed that the transfer of CD8+ T cells from sensitized and tolerant mice, but not CD4+ T cells, was able to protect naive mice from contact hypersensitivity, and this effect was found to be independent of the route of the tolerogenic treatment.

CD1d-restricted T cells 

γδ-T cells belong to a special T-cell subset that has been characterized by its capacity to recognize containing lipid compounds, mediated by the CD1d receptor. The evidence for allergens being recognized by CD1d receptors in γδ-T cells was shown in γδ-T cells obtained from peripheral blood samples and nasal mucosa tissue samples from individuals with allergy. Cloned human γδ-T cells from the subjects with allergy, compared with normal controls, proliferated and induced B-cell IgE production after being exposed in vitro to phosphatidyl-ethanolamine derived from cypress pollen, but not after exposure to lipids obtained from egg yolk, brain, liver, or olive.16 Elkhal et al17 explored the role of CD1d-restricted natural killer (NK) T cells in allergic dermatitis because of the role attributed to these cells in allergic asthma. They compared the results of skin sensitization by ovalbumin in normal mice and mice that do not express the CD1d receptor. Although they were able to show changes in airway sensitivity to methacholine, eosinophil infiltration, and IL-13 levels in bronchoalveolar lavage, they were not able to find similar differences in skin explants. The authors conclude the NKT cells play a different role in the pathogenesis of allergic inflammation in skin and the lung. Using tetramer technology with CD1d-βgal-ceramide, Pham-Thi et al18 confirmed the increased proportion of NKT cells in bronchoalveolar lavage in patients with asthma compared with controls and with patients with foreign body or infections.

Immune mechanisms of allergy 

Examining some lesser-known immunologic components in the allergic response, KleinJan et al19 presented evidence for the role of dendritic cells in the development of allergic rhinitis by documenting a significant increase of CD11c+ dendritic cells in nasal mucosa tissue of 22 patients with perennial allergic rhinitis compared with similar samples of 22 normal controls. The authors also worked with a mouse model counterpart in which depletion of CD11c+ dendritic cells was achieved by using diphtheria toxin linked to the molecule CD11c. After sensitization with ovalbumin and CD11c+ cell depletion, the TH2 cytokines IL-4, IL-5, and IL-13 were not detected, nor was ovalbumin-specific IgE. The development of asthma after sensitization with ovalbumin was also inhibited in a CD30 (TNF receptor superfamily, member 8) knockout mouse model.20 The importance of CD30 in the development of asthma in the mouse model was confirmed by blocking the interaction between CD30 and its ligand, CD153 (CD30L), with an anti-CD30 mAb. There was no evidence of induction of regulatory T cells, suggesting that CD30 may be a costimulatory molecule that induces TH2-mediated allergic responses.

A similar approach was used by Aoi et al21 in testing the function of IL-15 in allergic rhinitis. An IL-15 knockout mouse model was sensitized with ovalbumin, and after intranasal challenge, it showed the increased secretion of IgE and the TH2 cytokines IL-5 and IL-13, and with a lesser contribution, IL-4, and the eosinophil infiltration in nasal mucosa. Adoptive transfer of CD8+ T cells from ovalbumin-sensitized wild-type mice suppressed this response in wild-type mice, but not in IL-15 knockout mice. The administration of IL-15 at the time of challenge prevented the development of allergic rhinitis. Another similar approach investigated the function of the complement protein C3 in skin immune responses.22 C3 knockout mice sensitized with ovalbumin by epicutanous or intraperitoneal injection demonstrated decreased IL-4, IL-13, IL-5, and IFN-γ after ovalbumin stimulation, which was corrected after addition of C3 protein, suggesting both TH1 and TH2 are affected by C3 of complement. A mouse model that lacks expression of CCL19 and CCL21, ligands for CCR7, was investigated in the development of asthma using ovalbumin sensitization.23 Airway reactivity was similarly induced in both mutant and wild-type mice; however, there was significantly more inflammatory cells in the bronchoalveolar lavage of mutant mice, suggesting that CCR7 and its ligands may contribute to the clearance of cells from the airways. All of these proteins are potential targets for the development of novel therapeutic agents to control allergic diseases.

Another area of active research is the involvement of leukotrienes and prostaglandins in allergic disease. The expression of CysLT1, a leukotriene receptor, was shown in human B cells to increase 3-fold after activation with IL-4 and anti-CD40 antibody.24 This event resulted in increased calcium influx and increased IgE and IgG secretion after stimulation with the leukotriene D4. The inhibitory effect of IL-13 on prostaglandin E2 (PGE2) levels was investigated in epithelial cells obtained from endobronchial brushings of 5 patients with asthma and 3 normal controls.25 The experiments showed that IL-13 inhibits PGE2 synthesis and upregulates 1,5 prostaglandin dehydrogenase, an enzyme that metabolizes PGE2, and by decreasing PGE2 levels, possibly contributing to the inflammatory reaction induced by IL-13 in asthma. Gold et al26 found a statistical inverse correlation between eicosanoid acids levels in cord plasma and the proliferative responses of cord lymphocytes to phytohemagglutinin and to the allergens Bla g 2 and Der f 1 in a cohort of 192 healthy children. An increase of 0.5% of eicosapentanoic acid and of 1% of arachinoic acid was inversely correlated with allergen and ovalbumin proliferative response stimulation indexes. An inverse correlation was also found between the fatty acid cord plasma levels and the lowest quartile values of IFN-γ. The implications of these findings in the development of atopic disease are not clear, likely involving multiple genetic and environmental factors.

Current progress in high through-output technology allowed Liu et al27 to report an “immune transcriptome,” a collection of mRNA transcripts that are detected after activation of the different immune cells such as basophils. The authors were able to confirm the specificity of previously reported genes in the generation of immunity and identify new transcripts. This database is potentially useful for studies targeting individual genes, especially those genes that play master roles in complex allergic and immune responses.

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Advances in clinical immunology 

Advances in clinical immunology in 2006 included contributions in pathogenesis, diagnosis, treatment, and disease prevention. Kamchaisatian et al28 compared postimmunization antipneumococcal antibody titers in 22 HIV-infected children who had deficient antitetanus and antidiphtheria antibody responses with 95 immunocompetent children to establish the best criteria to determine antibody deficiency. Although these findings may not apply to other immunodeficiencies, they demonstrated the superiority of the criteria defined as “more than 4-fold increase in at least half of the titers measured.” The data in the normal control children interestingly show that approximately 35% of these controls may not respond to half the antigens with a 4-fold increase. A study of immune responses in children 1 to 3 years old of parents with asthma demonstrated that children had statistically significant differences in their cytokine levels with regard to sex: boys had increased IFN-γ, IL-5, and IL-13 levels, but not IL-10, compared with girls.29 CD103 was validated in human beings as another marker of regulatory T cells capable of expressing Foxp3 and inhibiting T-cell proliferative response to mitogens.30 Furthermore, it was shown that neonatal induction of regulatory T cells bearing the CD103 marker was more intense than a similar induction in adult T cells.

Other novel work included the description of the possible involvement of an autoantigen in asthma. Nahm et al31 found that 32 of 78 patients with severe asthma but only 2 of 58 normal controls had antibodies against α-enolase and cytokeratin 18. These antibodies are also present in other autoimmune disorders such as rheumatoid arthritis and systemic vasculitis. The authors concluded that although these antibodies may not participate in the etiology of asthma, they could be a good marker to identify patients with severe asthma.

With the Feld1-DRB10101 tetramer available, Bateman et al32 found that many individuals with cat allergy share the HLA type DRB10101 and demonstrated that most CD4+ T cells from these individuals expressed CCR7, CD62L, CD27, and CD28, which are characteristic of central memory T cells, and secreted IL-4 and IL-10. This work provides several tools with which to study immunologic memory responses to allergens.

Humanized mAbs and recombinant proteins are increasingly used to block molecular events involved in immunopathogenesis processes. Ballow33 reviewed the current targets for these therapeutic agents, with emphasis on those that contribute to the development of asthma. Considering that there are now more than 150 of such designed biological agents being tested or already in clinical use, most of them directed to control autoimmune and inflammatory disease, Ballow33 predicts that an increasing number of them may also apply to the treatment of asthma and other atopic diseases.

Primary immunodeficiencies 

A number of remarkable articles on primary immunodeficiencies (PIDs) were published in 2006. The most recent PID classification resulting from the 2005 meeting of the International Union of Immunological Societies was reported.34 This update was composed of 8 categories of more than 120 defined PIDs: combined T- and B-cell deficiencies, predominantly antibody deficiencies, well-defined immunodeficiencies, disease of immune dysregulation, congenital defects of phagocytes, defects of innate immunity, autoinflammatory disorders, and complement deficiencies. Caution should be exercised in establishing a specific PID on the basis of a single case report, as illustrated by the communication of Garcia-Laorden et al,35 who studied several hundred patients with recurrent respiratory infections and suitable control subjects to find mutations in the mannose-binding lectin-associated serine proteinase 2 gene, which is essential in the lectin pathway of complement activation. The only 2 individuals with homozygous mutation and low expression of mannose-binding lectin-associated serine proteinase 2 protein were healthy individuals, suggesting that the genetic defect has low clinical penetrance and that other complement activation mechanisms replace its function. Castigli and Geha36 reviewed the advances in the molecular understanding of some forms of common variable immunodeficiency (CVID), focusing in the transmembrane activator and calcium-modulator and cyclophilin ligand interactor defect, which is estimated to be responsible for 10% of the CVID cases. CD8+ T-cell lymphoproliferative disease was reported in a single patient with CVID as an event that should be included in the list of complications seen in this PID.37 Lin et al38 described an 18-year-old boy with CVID and chronic granulomas of the left arm not responsive to treatment with antibiotics, intravenous immunoglobulin, antifungal agents, systemic and intralesional steroids, IFN-γ, immunosuppressants, localized radiation therapy, and surgical excision. The skin lesions improved after treatment with the systemic TNF-α inhibitor etanercept for 1 year. Notarangelo et al39 reviewed the immunodeficiency disorders resulting from impaired class-switch recombination, and Ochs and Thrasher40 examined the advances in the Wiskott-Aldrich syndrome (WAS), the X-linked neutropenia, and the X-linked thrombocytopenia, disorders resulting from different mutations in the gene encoding the WAS protein. The therapeutic use of intravenous immunoglobulins (IGIVs) was discussed by expert members of the Primary Immunodeficiency Committee of the American Academy of Asthma, Allergy & Immunology.41 They reviewed the evidence supporting the use of IGIVs for immunodeficiency diseases and inflammatory conditions such as Kawasaki disease and Guillain-Barre syndrome. Their recommendations are useful to practitioners treating patients with these challenging diseases.

Other reports on PID included a review of lymphocyte markers of 39 patients with DiGeorge syndrome, demonstrating that T-cell receptor excision circle counts were the best correlate for cellular function as measured by lymphoproliferative response to mitogens.42 Clinical experience in PIDs was enriched with several case reports. Roifman et al43 described Omenn syndrome in 2 children with mutations in the gene encoding the RNA component of mitochondrial RNAse processing, responsible for the cartilage-hair hypoplasia syndrome. Cac and Ballas44 described a patient with deficient NK cell killing activity and periungual warts resistant to conventional treatment who responded to 9-month therapy with IFN-α.

Drug allergy 

Beeler et al45 examined 5 patients with history of severe allergic reaction to amoxicillin, carbamazepine, phenytoin, sulfamethoxazole, and vancomycin 4 months to 12 years after the reaction. Using drug-induced lymphoproliferative assays and cytokine expression, the authors determined that about 1 in 250 to 5000 CD4+ T cells present in those individuals were specific to the offending drug, suggesting a response that is long-lasting. Wu et al46 demonstrated the in vitro cross-reactivity of carbamazepine and its metabolites in 39 patients with drug hypersensitivity to carbamazepine, supporting the recommendation of avoiding related drugs in patients with drug allergy. Rodriguez-Pena et al47 showed the involvement of dendritic cells in drug allergy to amoxicillin by showing increases of activation and phagocytosis after dendritic cells from subjects with drug allergy were exposed to amoxicillin, compared with dendritic cells from healthy controls.

Angioedema 

The first case of hereditary angioedema (HAE) caused by a homozygous mutation in the C1INH gene was reported by Blanch et al.48 The authors pointed out the recognition of this condition for therapeutic management, because androgens may not be effective to increase the C1 inhibitor and the inhibitor replacement would be necessary. In an accompanying editorial, Frank and Atkinson49 discussed this case report to point out remarkable features, such as the low frequency of HAE episodes that could be related to the nature of the mutation, allowing partial C1INH protein expression. The self-administration of the C1 inhibitor was indicated on demand in 31 patients and as prophylaxis in 12 patients.50 The authors conclude that there was a significant reduction of the time of symptoms resolution and suggest self-administration is a viable alternative of treatment. The potential relief from anaphylaxis using new therapeutic agents for HAE was illustrated by the report of Caballero and Lopez-Serrano,51 describing a patient with HAE who developed anaphylaxis after receiving the kalikrein inhibitor DX88.

HIV infection 

HIV research continues to make progress in the improvement of current therapies, particularly in the treatment of multidrug-resistant HIV strains and debilitating drug adverse effects. Feeney et al52 reported the first case of a patient with perinatally acquired HIV infection who was treated for 10 years with 3 different regimens of dual nucleoside reverse-transcriptase inhibitors and then self-discontinued therapy. After 5 years without treatment, the patient continued with normal CD4+ T cell counts and undetectable HIV plasma viremia. In an effort to identify host factors determining HIV disease progression, this patient was found to be heterozygous for the CCR5 gene deletion, known to be associated with slow disease progression, and had strong anti-HIV cellular immunity, as measured by TH1-type cytokine production and in vitro lymphoproliferation in response to exposure to HIV proteins. Saitoh et al53 studied the use of TRECs as a predictive marker for maintenance of normal CD4+ T-cell count in patients with HIV receiving highly active antiretroviral therapy who continue to have a high intracellular HIV DNA burden. This study emphasized the role of the thymus in the regulation of CD4+ T-cell homeostasis. Two articles reported progress in the development of new therapeutic agents. Shearer et al54 demonstrated the in vitro susceptibility of pediatric HIV isolates to 2 compounds, an anti-CCR5 mAb and a CD4-immunoglobulin fusion protein, both of which block HIV cell entry. Williamson et al55 reported another cell entry blocker, the epigallocatechin gallate, the major polyphenol found in green tea. Using crystallography technology, they were able to pinpoint the epigallocatechin gallate binding site on the CD4 molecule. Also, they achieved significant inhibition of HIV gp120 binding to CD4+ T cells with physiologically relevant concentrations in a dose-dependent manner.

Infection and immunity 

The role of host defenses in the fight against infectious diseases continues to be expanded and defined. New approaches in the investigation of immunity against viruses, bacteria, and parasites have been published. Parrino and Graham56 reviewed the history of smallpox disease, its eradication in 1980 after worldwide use of smallpox vaccine, and current challenges to develop a modern vaccine for a potential outbreak, a threat that is possible under the concept of bioterrorism. Glezen57 discussed the benefits of the inactivated and live vaccines for influenza virus in the general population and with emphasis in children with asthma, pointing out the evidence indicating their safety and the reduction of medical encounters and medication use by 22% to 45%. Prompted by an outbreak of mumps in the US Midwest in 2006, Kancherla and Hanson58 briefly reviewed this preventable disease and possible immune and nonimmune causes of vaccine failure. These authors concluded that poor adherence to current guidelines for prevention were the most likely factor that resulted in this outbreak and emphasized the need of the highest compliance of the community with vaccination policies to avoid future similar episodes.

Cardona et al59 demonstrated the increased expression of the ligand for the glucocorticoid-induced TNF receptor–related protein in human monocytes exposed to staphylococcal exotoxin B (SEB), a known superantigen. The increased expression of glucocorticoid-induced TNF receptor–related ligand suppressed the natural regulatory T-cell inhibitory function on effector T cells and thus contributed to the immune dysregulation associated to superantigens exposure. Mandron et al60 found that exposure of human monocytes to SEB also resulted in increased IL-2 secretion, but not IL-12, driving naive T lymphocytes to differentiate into the TH2 phenotype. These human monocyte responses to SEB provide clues to understand further the pathogenesis of inflammatory responses associated with SEB.

Similarly, the TH2 phenotype was found to be more prevalent in T cells obtained from the bronchoalveolar lavage of patients with cystic fibrosis (CF) infected with Pseudomona aeruginosa compared with noninfected patients with CF and with normal volunteers.61 The authors suggest that strategies to control TH2 inflammatory responses may be therapeutic. The immunologic mechanisms of this observation may be further explored in animal models, such as one proposed by Saadane et al,62 who reported a mouse model for CF that was used to show the inflammatory response and persistent nuclear factor-κB activation induced by P aeruginosa infection.

Cellular immune responses were investigated in 10 patients with extrapulmonary tuberculosis, 24 patients with previous pulmonary tuberculosis, and 30 patients with latent tuberculosis infections who were HIV-negative.63 The authors found that patients with previous history of tuberculosis had decreased number of CD4+ T cells and lower in vitro secretion of inflammatory cytokines (IL-1, TNF, IFN) after phytohemagglutinin stimulation than patients who had latent infection. In addition, patients who developed extrapulmonary tuberculosis had the lowest cytokine levels measured in unstimulated lymphocytes. These results suggest subtle deficiencies in immune mechanisms to activate the cellular response (eg, TLR signaling). Fuller et al64 described the immune response in 6 normal volunteers who received a live attenuated vaccine for tularemia, caused by Francisella tularensis. They pointed out the importance of innate immunity on the basis of their findings of increased peripheral blood cell numbers in the first 24 hours, which were predominantly NK and γδ-T cells.

In the field of antiparasite immunity, Mitre and Nutman65 examined 30 patients with filarial infections before and after antiworm treatment. They reported that after a long period (11-37 months) and with no possible re-exposure, specific antifilarial IgE remained detectable in their serum with capacity to activate basophils for histamine release, thus supporting the concept of the long-term half-life of specific IgE responses.

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Conclusion 

The fields of basic and clinical immunology continue their exponential scientific progress to help us better understand the pathogenesis, diagnosis, treatment, and prevention of human disease. Innate immunity, specifically the biology of TLRs, is actively investigated to increase the specificity of vaccines for infections and for immunomodulation in allergic diseases. The CD1d-restricted T cells, with specificity for antigens containing lipid motifs, have been shown to play an essential role in the inflammatory response in asthma. Dendritic cells are investigated in their role to determine the development of allergic responses. Significant progress in clinical immunology included the identification of the molecular basis of more than 120 primary immunodeficiencies, the progress in the development of new anti-HIV drugs that block cell entry, and the application of new immune concepts for the understanding of infectious disease pathogenesis and vaccine development, such as the role of innate immunity and the stimulation of TH2 responses by P aeruginosa infection in patients with CF.

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 Supported by National Institutes of Health grants AI269441, AI36211, HD52102, RR0188, HD079533, HL72705, HD78522, and RAT003084A and contract AI41089; the Pediatric Research and Education Fund, Baylor College of Medicine; and the David Fund, Pediatrics AIDS Fund, and Immunology Research Fund, Texas Children's Hospital.Disclosure of potential conflict of interest: The authors have declared that they have no conflict of interest.

PII: S0091-6749(07)01026-3

doi:10.1016/j.jaci.2007.05.031

The Journal of Allergy and Clinical Immunology
Volume 120, Issue 2 , Pages 263-270, August 2007

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